News

Headline

CMV infections: plants beaten at their own game

Plants have evolved very efficient processes to protect themselves from herbivore and pathogen attacks. The jasmonate signaling pathway is a nice example of such a process. Jasmonate is lipid-based plant hormone, with a similar structure to animal prostaglandins. In the absence of jasmonate, JAZ (jasmonate ZIM domain) proteins bind to downstream transcription factors, hence silencing the expression of plant defense genes against herbivores. Following mechanical wounding or herbivory, jasmonate biosynthesis is rapidly activated. In the presence of jasmonate or its bioactive derivatives, JAZ proteins are degraded via the proteasome, freeing transcription factors for expression of genes needed for defense. Another indirect result of jasmonate signaling is the emission of volatile jasmonate-derived compounds. These can travel to nearby plants and elevate levels of transcripts related to wound response. This emission can further upregulate jasmonate biosynthesis and cell signaling, thereby inducing nearby plants to prime their defenses in case of herbivory.

Plant defense against viruses is also outstanding. The primary defense against, for instance, cucumber mosaic virus (CMV) is directed by antiviral RNA interference (RNAi) guided by the virus-derived small interfering RNAs. This strategy, known as post-transcriptional gene silencing, limits the accumulation of viral RNAs.

Obviously, viruses have developed counter-defense strategies. CMV encodes a viral suppressor of host RNAi, the 2b protein, which acts at two levels. It directly interacts with both the RNA and protein components of the plant RNA silencing machinery. By binding to double-stranded RNAs, it inhibits the production of viral siRNAs. By interacting with the argonaute protein, it prevents argonaute slicer activity. Once the host defense is neutralized, the virus can go on replicating, but that is not the end of the story. After replication, the virus needs to propagate to other plants, and to do so, it has to attract insect vectors, in the case of CMV, aphids.

At this stage, CMV again uses the 2b protein. This time, the 2b protein acts at the level of the jasmonate signaling pathway, inhibiting its activation. The 2b protein binds JAZ proteins and prevents their degradation, which would otherwise turn on the jasmonate signaling pathway. Through a yet unknown mechanism, the repression of the jasmonate signaling pathway leads to increased odor-dependent aphid attraction. Once the insects settle down on the infected plant, they suck sap and concomitantly pick up viruses to transmit them later on to other plants.

The astonishingly multifunctional CMV 2b protein has been manually annotated in the Swiss-Prot section of UniProtKB and is now publicly available.

UniProtKB news

Changes to the controlled vocabulary of human diseases

New diseases:

• Amegakaryocytic thrombocytopenia, congenital, 2
• Amyotrophic lateral sclerosis 28
• Arrhythmogenic cardiomyopathy with variable ectodermal abnormalities
• Auriculocondylar syndrome 2B
• Auriculocondylar syndrome 4
• Autoimmune disease, multisystem, infantile-onset, 3
• Autoinflammatory disease, multisystem, with immune dysregulation, X-linked
• Becker nevus syndrome
• Birt-Hogg-Dube syndrome 2
• Bleeding disorder, platelet-type, 25
• Breast-ovarian cancer, familial, 5
• Cardiomyopathy, dilated, 2I
• Chronic recurrent multifocal osteomyelitis 3
• Combined oxidative phosphorylation deficiency 58
• Congenital disorder of glycosylation 2AA
• Congenital smooth muscle hamartoma, with or without hemihypertrophy
• Cranial dysinnervation disorder, congenital, with absent corneal reflex and developmental delay
• Craniofacial microsomia 2
• Developmental and epileptic encephalopathy 111
• Disabling pansclerotic morphea of childhood
• Dystonia 22, adult-onset
• Dystonia 22, juvenile-onset
• Encephalitis, acute, infection-induced, 12
• Epilepsy, early-onset, 3, with or without developmental delay
• Fliedner-Zweier syndrome
• Hemolytic uremic syndrome, atypical, 8, with rhizomelic short stature
• Hyper-IgE syndrome 6, autosomal dominant, with recurrent infections
• Ichthyosis with erythrokeratoderma
• Immune dysregulation, autoimmunity, and autoinflammation
• Immunodeficiency 112
• Intellectual developmental disorder, autosomal dominant 72
• Intellectual developmental disorder, autosomal dominant 73
• Intellectual developmental disorder, X-linked 112
• Lipomatosis, multiple symmetric, with or without peripheral neuropathy
• Megalencephalic leukoencephalopathy with subcortical cysts 3
• Megalencephalic leukoencephalopathy with subcortical cysts 4, remitting
• Myopathy, distal, 3
• Myopathy with rimmed ubiquitin-positive autophagic vacuolation, autosomal dominant
• Neurodevelopmental disorder with dysmorphic facies and behavioral abnormalities
• Neurodevelopmental disorder with hypotonia and speech delay, with or without seizures
• Neurodevelopmental disorder with impaired language, behavioral abnormalities, and dysmorphic facies
• Neurodevelopmental disorder with language delay and variable cognitive abnormalities
• Neurodevelopmental disorder with microcephaly and movement abnormalities
• Neurodevelopmental disorder with motor and language delay, ocular defects, and brain abnormalities
• Neurodevelopmental disorder with motor regression, progressive spastic paraplegia, and oromotor dysfunction
• Neuronopathy, distal hereditary motor, autosomal recessive 9
• Neuronopathy, distal hereditary motor, autosomal dominant 11
• Neutropenia, severe congenital, 10, autosomal recessive
• Oculopharyngeal muscular dystrophy 2
• Parkinson disease 25, autosomal recessive early-onset, with impaired intellectual development
• Prostate cancer, hereditary, 9
• Spastic paraplegia 18A, autosomal dominant
• Spastic paraplegia 72B, autosomal recessive
• Spermatogenic failure 85
• Spermatogenic failure 86
• Spermatogenic failure 87
• Taurodontism, microdontia, and dens invaginatus
• Thrombocytopenia 8, with dysmorphic features and developmental delay
• Thrombocytopenia 9
• Thrombocytopenia 10
• Variegate porphyria, childhood-onset
• Woolly hair-skin fragility syndrome
• Xerosis and growth failure with immune and pulmonary dysfunction syndrome
• Ziegler-Huang syndrome

Modified diseases:

• Alport syndrome 3, autosomal dominant -> Alport syndrome 3A, autosomal dominant
• Auriculocondylar syndrome 2 -> Auriculocondylar syndrome 2A
• Beukes familial hip dysplasia -> Beukes hip dysplasia
• Birt-Hogg-Dube syndrome -> Birt-Hogg-Dube syndrome 1
• Congenital amegakaryocytic thrombocytopenia -> Amegakaryocytic thrombocytopenia, congenital, 1
• Congenital cataracts, hearing loss, and neurodegeneration -> Huppke-Brendel syndrome
• Craniofacial microsomia -> Craniofacial microsomia 1
• Distal spinal muscular atrophy, autosomal recessive, 2 -> Neuronopathy, distal hereditary motor, autosomal recessive 2
• Distal spinal muscular atrophy, autosomal recessive, 4 -> Neuronopathy, distal hereditary motor, autosomal recessive 4
• Distal spinal muscular atrophy, autosomal recessive, 5 -> Neuronopathy, distal hereditary motor, autosomal recessive 5
• Distal spinal muscular atrophy, autosomal recessive, 6 -> Neuronopathy, distal hereditary motor, autosomal recessive 6
• Distal spinal muscular atrophy, X-linked, 3 -> Neuronopathy, distal hereditary motor, X-linked
• Dystonia, juvenile-onset -> Dystonia-deafness syndrome 1
• Epilepsy, early-onset, vitamin B6-dependent -> Epilepsy, early-onset, 1, vitamin B6-dependent
• Epilepsy, early-onset, with or without developmental delay -> Epilepsy, early-onset, 2, with or without developmental delay
• Hemolytic uremic syndrome atypical 1 -> Hemolytic uremic syndrome, atypical, 1
• Hemolytic uremic syndrome atypical 2 -> Hemolytic uremic syndrome, atypical, 2
• Hemolytic uremic syndrome atypical 3 -> Hemolytic uremic syndrome, atypical, 3
• Hemolytic uremic syndrome atypical 4 -> Hemolytic uremic syndrome, atypical, 4
• Hemolytic uremic syndrome atypical 5 -> Hemolytic uremic syndrome, atypical, 5
• Hemolytic uremic syndrome atypical 6 -> Hemolytic uremic syndrome, atypical, 6
• Hemolytic uremic syndrome atypical 7 -> Hemolytic uremic syndrome, atypical, 7
• Hyper-IgE recurrent infection syndrome 1, autosomal dominant -> Hyper-IgE syndrome 1, autosomal dominant, with recurrent infections
• Hyper-IgE recurrent infection syndrome 2, autosomal recessive -> Hyper-IgE syndrome 2, autosomal recessive, with recurrent infections
• Hyper-IgE recurrent infection syndrome 3, autosomal recessive -> Hyper-IgE syndrome 3, autosomal recessive, with recurrent infections
• Hyper-IgE recurrent infection syndrome 4A, autosomal dominant -> Hyper-IgE syndrome 4A, autosomal dominant, with recurrent infections
• Hyper-IgE recurrent infection syndrome 4B, autosomal recessive -> Hyper-IgE syndrome 4B, autosomal recessive, with recurrent infections
• Hyper-IgE recurrent infection syndrome 5, autosomal recessive -> Hyper-IgE syndrome 5, autosomal recessive, with recurrent infections
• Intellectual developmental disorder, autosomal dominant 35 -> Houge-Janssens syndrome 1
• Intellectual developmental disorder, autosomal dominant 36 -> Houge-Janssens syndrome 2
• Intellectual developmental disorder with cardiac arrhythmia -> Lodder-Merla syndrome, type 1, with impaired intellectual development and cardiac arrhythmia
• Interleukin 1 receptor antagonist deficiency -> Chronic recurrent multifocal osteomyelitis 2, with periostitis and pustulosis
• Keratoderma, palmoplantar, epidermolytic -> Palmoplantar keratoderma, epidermolytic, 1
• Kohlschutter-Tonz syndrome-like -> Den Hoed-de Boer-Voisin syndrome
• Language delay and attention deficit-hyperactivity disorder/cognitive impairment with or without cardiac arrhythmia -> Lodder-Merla syndrome, type 2, with developmental delay and with or without cardiac arrhythmia
• Leber hereditary optic neuropathy, autosomal recessive -> Leber hereditary optic neuropathy, autosomal recessive 1
• Leukoencephalopathy, megalencephalic, with subcortical cysts, 1 -> Megalencephalic leukoencephalopathy with subcortical cysts 1
• Leukoencephalopathy, megalencephalic, with subcortical cysts, 2A -> Megalencephalic leukoencephalopathy with subcortical cysts 2A
• Li-Fraumeni syndrome 2 -> Tumor predisposition syndrome 4
• Melanoma, cutaneous malignant 10 -> Tumor predisposition syndrome 3
• Nemaline myopathy 11 -> Congenital myopathy 24
• Nephrotic syndrome 14 -> RENI syndrome
• Neurodevelopmental disorder and language delay with or without structural brain abnormalities -> Houge-Janssens syndrome 3
• Neurodevelopmental disorder with gait disturbance, dysmorphic facies, and behavioral abnormalities, X-linked -> Hijazi-Reis syndrome
• Neurodevelopmental disorder with poor growth, spastic tetraplegia, and hearing loss -> Birk-Aharoni syndrome
• Neurofibromatosis 2 -> Schwannomatosis, vestibular
• Neuronopathy, distal hereditary motor, 2A -> Neuronopathy, distal hereditary motor, autosomal dominant 2
• Neuronopathy, distal hereditary motor, 2B -> Neuronopathy, distal hereditary motor, autosomal dominant 3
• Neuronopathy, distal hereditary motor, 2C -> Neuronopathy, distal hereditary motor, autosomal dominant 4
• Neuronopathy, distal hereditary motor, 2D -> Neuronopathy, distal hereditary motor, autosomal dominant 6
• Neuronopathy, distal hereditary motor, 5A -> Neuronopathy, distal hereditary motor, autosomal dominant 5
• Neuronopathy, distal hereditary motor, 5B -> Neuronopathy, distal hereditary motor, autosomal dominant 12
• Neuronopathy, distal hereditary motor, 5C -> Neuronopathy, distal hereditary motor, autosomal dominant 13
• Neuronopathy, distal hereditary motor, 6 -> Neuronopathy, distal hereditary motor, autosomal recessive 1
• Neuronopathy, distal hereditary motor, 7A -> Neuronopathy, distal hereditary motor, autosomal dominant 7
• Neuronopathy, distal hereditary motor, 7B -> Neuronopathy, distal hereditary motor, autosomal dominant 14
• Neuronopathy, distal hereditary motor, 8 -> Neuronopathy, distal hereditary motor, autosomal dominant 8
• Neuronopathy, distal hereditary motor, 9 -> Neuronopathy, distal hereditary motor, autosomal dominant 9
• Neuronopathy, distal hereditary motor, 10 -> Neuronopathy, distal hereditary motor, autosomal dominant 10
• Neuropathy, hereditary motor, with myopathic features -> Neuronopathy, hereditary motor, autosomal recessive 7
• Oculopharyngeal muscular dystrophy -> Oculopharyngeal muscular dystrophy 1
• Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures -> Cortical dysplasia, complex, with other brain malformations 15
• Paragangliomas 1 -> Pheochromocytoma/paraganglioma syndrome 1
• Paragangliomas 2 -> Pheochromocytoma/paraganglioma syndrome 2
• Paragangliomas 3 -> Pheochromocytoma/paraganglioma syndrome 3
• Paragangliomas 4 -> Pheochromocytoma/paraganglioma syndrome 4
• Paragangliomas 5 -> Pheochromocytoma/paraganglioma syndrome 5
• Paragangliomas 6 -> Pheochromocytoma/paraganglioma syndrome 6
• Paragangliomas 7 -> Pheochromocytoma/paraganglioma syndrome 7
• Paramyotonia congenita of von Eulenburg -> Paramyotonia congenita
• Pyridoxine-dependent epilepsy -> Epilepsy, early-onset, 4, vitamin B6-dependent
• Polymicrogyria, bilateral frontoparietal -> Cortical dysplasia, complex, with other brain malformations 14A (bilateral frontoparietal)
• Polymicrogyria, bilateral perisylvian, autosomal recessive -> Cortical dysplasia, complex, with other brain malformations 14B (bilateral perisylvian)
• Sorbitol dehydrogenase deficiency with peripheral neuropathy -> Neuronopathy, distal hereditary motor, autosomal recessive 8
• Spastic paraplegia 18, autosomal recessive -> Spastic paraplegia 18B, autosomal recessive
• Spastic paraplegia 72 -> Spastic paraplegia 72A, autosomal dominant

Deleted diseases:

• Glioma 9
• Unilateral palmoplantar verrucous nevus

Changes to the controlled vocabulary for PTMs

New term for the feature key 'Lipidation' ('LIPID' in the flat file):

• GPI-anchor amidated isoleucine

Headline

Vitamin K beyond coagulation

The involvement of vitamin K in blood clotting has been known for about a century now (see UniProt headline). Vitamin K is made by plants, and is found in highest amounts in green leafy vegetables, in which it is directly involved in photosynthesis. In animal cells, the vitamin undergoes the so-called canonical vitamin K cycle, in which it is first reduced into its active form by vitamin K epoxide reductase (VKOR). It then becomes the cosubstrate for vitamin K-dependent gamma-carboxylase (GGCX), which catalyzes gamma-carboxylation of glutamate residues in target proteins, including several blood factor proteins, leading to initiation of the blood coagulation cascade. During the reaction, vitamin K is oxidized, but it is restored back to active vitamin K by VKOR, being continuously recycled.

Anticoagulant drugs, like warfarin, inhibit VKOR, blocking vitamin K recycling and depleting active vitamin K stores. Prescription of warfarin is tricky, as overdosage can cause life-threatening bleeding. The standard clinical treatment for warfarin poisoning is the administration of a high dose of vitamin K, which is well-tolerated and does not exhibit any toxicity. During the treatment, blood clotting is enabled through the action of a warfarin-resistant reductase, whose identity was long elusive.

The solution of the mystery came from a study focused on a different topic, namely ferroptosis. Ferroptosis is an iron-dependent form of cell death, characterized by the accumulation of lipid-based reactive oxygen species that results in membrane damage. It is thought to be one of the most widespread and ancient forms of regulated cell death. Cells have evolved a number of highly efficient redox systems that counteract uncontrolled lipid peroxidation. One of them is mediated by the ferroptosis suppressor protein 1 (FSP1 or AIFM2) in the presence of ubiquinone (also known as coenzyme Q10, CoQ10): reduced CoQ10 traps lipid peroxyl radicals that mediate lipid peroxidation, whereas FSP1 catalyzes the regeneration of CoQ10 using NAD(P)H. Vitamin K shares structural similarities with CoQ10, hence testing FSP1's activity on vitamin K seemed a natural extension. The results are striking: reduced vitamin K produced by FSP1 actively prevents lipid peroxidation. The reaction is not sensitive to warfarin.

The discovery of a new function for vitamin K, as a guardian against ferroptosis, may also have an impact on clinical practice. As a consequence of vasoconstriction, thrombosis, or embolism, tissues can experience a restriction in blood supply, called ischemia, causing a shortage of oxygen that is needed for cellular metabolism. Paradoxically, restoration of blood flow to previously ischemic tissues can cause the exacerbation of cellular dysfunction and death through the induction of oxidative stress and ferroptosis, a phenomenon known as ischemia-reperfusion injury (IRI). In an IRI mouse model, Mishima et al. showed that vitamin K supplementation could prevent tissue-damaging inflammation in the liver or kidneys. Vitamin K could also prevent ferroptosis in neurons.

While waiting for future clinical trials, you can always visit our updated vertebrate FSP1/AIFM2 entries.

UniProtKB news

Cross-references to EMDB

Cross-references have been added to the EMDB database, the Electron Microscopy Data Bank.

EMDB is available at https://www.ebi.ac.uk/emdb.

The format of the explicit links is:

Resource abbreviation	EMDB
Resource identifier	Resource identifier

Example: Q7Z7F7

Show all entries having a cross-reference to EMDB.

Text format

Example: Q7Z7F7

DR   EMDB; EMDB-16898; -.

XML format

Example: Q7Z7F7

<dbReference type="EMDB" id="EMDB-16898"/>

RDF format

Example: Q7Z7F7

uniprot:Q7Z7F7
  rdfs:seeAlso <http://purl.uniprot.org/emdb/EMDB-16898> .
<http://purl.uniprot.org/emdb/EMDB-16898>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/EMDB> .

Cross-references to JaponicusDB

Cross-references have been added to the JaponicusDB database, the Schizosaccharomyces japonicus model organism database.

JaponicusDB is available at https://www.japonicusdb.org.

The format of the explicit links is:

Resource abbreviation	JaponicusDB
Resource identifier	Resource identifier
Optional information 1	Gene designation

Example: B6K366

Show all entries having a cross-reference to JaponicusDB.

Text format

Example: B6K366

DR   JaponicusDB; SJAG_03048; cdc2.

XML format

Example: B6K366

<dbReference type="JaponicusDB" id="SJAG_03048">
  <property type="gene designation" value="cdc2"/>
</dbReference>

RDF format

Example: B6K366

uniprot:B6K366
  rdfs:seeAlso <http://purl.uniprot.org/japonicusdb/SJAG_03048> .
<http://purl.uniprot.org/japonicusdb/SJAG_03048>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/JaponicusDB> ;
  rdfs:comment "cdc2" .

Changes to the controlled vocabulary of human diseases

New diseases:

• Arrhythmogenic right ventricular dysplasia, familial, 15
• Auditory neuropathy, autosomal dominant 2
• Autoinflammatory disease, systemic, with vasculitis
• Bazex-Dupre-Christol syndrome
• Cardiomyopathy, dilated, 1PP
• Cataracts, hearing impairment, nephrotic syndrome, and enterocolitis 1
• Cataracts, hearing impairment, nephrotic syndrome, and enterocolitis 2
• Ciliary dyskinesia, primary, 51
• Dystonia 37, early-onset, with striatal lesions
• Glycine encephalopathy 2
• Hypersulfaturia
• Multiple mitochondrial dysfunctions syndrome 7
• Muscular dystrophy, limb-girdle, autosomal recessive 28
• Nemaline myopathy 5B, autosomal recessive, childhood-onset
• Nemaline myopathy 5C, autosomal dominant
• Nephrolithiasis, calcium oxalate, 2, with nephrocalcinosis
• Neurodevelopmental disorder with intracranial hemorrhage, seizures, and spasticity
• Oocyte/zygote/embryo maturation arrest 20
• Palmoplantar keratoderma, epidermolytic, 2
• Pulmonary fibrosis, and/or bone marrow failure syndrome, telomere-related, 9
• Retinitis pigmentosa 97
• Spastic paraplegia 89, autosomal recessive
• Spastic paraplegia 90A, autosomal dominant
• Spastic paraplegia 90B, autosomal recessive
• Spermatogenic failure 84

Modified diseases:

• Epidermolytic hyperkeratosis -> Epidermolytic hyperkeratosis 1
• Mitochondrial complex V deficiency, nuclear type 4 -> Mitochondrial complex V deficiency, nuclear type 4B
• Nemaline myopathy 4 -> Congenital myopathy 23
• Nemaline myopathy 5 -> Nemaline myopathy 5A, autosomal recessive, severe infantile
• Nephrolithiasis, calcium oxalate -> Nephrolithiasis, calcium oxalate, 1
• Pulmonary fibrosis, and/or bone marrow failure, telomere-related, 1 -> Pulmonary fibrosis, and/or bone marrow failure syndrome, telomere-related, 1
• Pulmonary fibrosis, and/or bone marrow failure, telomere-related, 3 -> Pulmonary fibrosis, and/or bone marrow failure syndrome, telomere-related, 3
• Pulmonary fibrosis, and/or bone marrow failure, telomere-related, 4 -> Pulmonary fibrosis, and/or bone marrow failure syndrome, telomere-related, 4
• Pulmonary fibrosis, and/or bone marrow failure, telomere-related, 5 -> Pulmonary fibrosis, and/or bone marrow failure syndrome, telomere-related, 5
• Pulmonary fibrosis, and/or bone marrow failure, telomere-related, 6 -> Pulmonary fibrosis, and/or bone marrow failure syndrome, telomere-related, 6
• Pulmonary fibrosis, and/or bone marrow failure, telomere-related, 7 -> Pulmonary fibrosis, and/or bone marrow failure syndrome, telomere-related, 7
• Pulmonary fibrosis, and/or bone marrow failure, telomere-related, 8 -> Pulmonary fibrosis, and/or bone marrow failure syndrome, telomere-related, 8

Deleted disease:

• Cap myopathy 2

Changes to the controlled vocabulary for PTMs

New terms for the feature key 'Modified residue' ('MOD_RES' in the flat file):

• Aspartate methyl ester
• N6-acetyl-N6-methyllysine

Headline

Hush, little ribosome

Often when we think of translation, we often focus so intently on the protein we are interested in that we forget that, at the microscopic scale, the machinery involved to produce proteins is huge. Most cells contain millions of ribosomes and egg cells contain even orders of magnitude more. Translation is one of the most energy-costly processes. It has been estimated to require ~5 ATP per peptide bond or ~2,300 ATP per typical protein synthesized. That is why the whole process has to be tightly regulated not only at the level of single proteins, but also on a large scale. For instance, egg cells have to quietly await fertilization, to save energy and protect mRNAs and ribosomes, and to be ready for full-blown action in the first steps of embryogenesis. Translational repression has been extensively studied from the RNA standpoint. At the mRNA level, several mechanisms may account for translation dampening, often linked to 3'UTR sequences, including shortening the poly(A) tail, or interfering with the formation of the eIF4F complex. However, the contribution of ribosomes to the global translation repression process was not investigated until recently.

In zebrafish, as in other vertebrates, translation is repressed in eggs. It resumes about 3 hours after fertilization. At the ribosome level, this is reflected by the presence of almost exclusively monosomes before fertilization. The proportion of polysomes starts to increase from 3 to 6 hours after fertilization onwards. Four proteins have been shown to be associated with the "dormant" ribosomes (monosomes): death-associated protein-like 1 homolog (dap1b), intracellular hyaluronan-binding protein 4 (habp4), elongation factor 2b (eef2b) and eukaryotic translation initiation factor 5A-1 (eif5a), forming two modules, eef2b-habp4 and eif5a-dap1b, that bind distinct sites on the same ribosome.

In active ribosomes, eef2 mediates ribosomal translocation along the mRNA and transiently interacts with the tRNA-mRNA complex at the aminoacyl (A) site of the ribosome. In dormant ribosomes, habp4 binds to the mRNA-entry channel and sequesters eef2 at the A site and blocks the interaction sites of the tRNA-mRNA complex. eif5a normally promotes translation elongation and termination and binds between the exit (E) and peptidyl (P) sites of the ribosome. In dormant ribosomes, dap1b sits in the polypeptide exit tunnel (PET), where newly formed proteins normally emerge, and forms a kind of plug. Its C-terminus occupies the same position as the C-terminal residue of a nascent peptide chain and forms a hydrogen bond with the hypusine residue of eIF5a, a residue that is essential for eif5a function.

Although habp4 binding to the mRNA-entry channel is incompatible with translation, the current hypothesis is that its main function is instead to stabilize ribosomes, and that it is dap1b that predominantly carries the translation repression function.

Can these observations be extended to other animals? Experiments carried out in Xenopus laevis gave similar results. Furthermore, in vitro translation assays in rabbit reticulocyte lysates showed that not only recombinant zebrafish dap1b, but also orthologous proteins in other organisms, including Xenopus, human (where the orthologous gene is called SERBP1), and even C.elegans, all repress translation.

If contrary to ribosomes you did not fall asleep while reading this headline, you can consult the UniProtKB/Swiss-Prot entries for habp4, dap1b/SERBP1, as well as eef2b/EEF2 and eif5a in our new release.

UniProtKB news

Cross-references to Pumba

Cross-references have been added to Pumba, a database of electrophoretic reference migration patterns.

Pumba is available at https://pumba.dcsr.unil.ch.

The format of the explicit links is:

Resource abbreviation	Pumba
Resource identifier	UniProtKB accession number

Example: P11274

Show all entries having a cross-reference to Pumba.

Text format

Example: P11274

DR   Pumba; P11274; -.

XML format

Example: P11274

<dbReference type="Pumba" id="P11274"/>

RDF format

Example: P11274

uniprot:P11274
  rdfs:seeAlso <http://purl.uniprot.org/pumba/P11274> .
<http://purl.uniprot.org/pumba/P11274>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/Pumba> .

Changes to the controlled vocabulary of human diseases

New diseases:

• Cerebroretinal microangiopathy with calcifications and cysts 3
• Charcot-Marie-Tooth disease, axonal, 2GG
• Combined low LDL and fibrinogen
• Intellectual developmental disorder, autosomal recessive 79
• Mitochondrial complex V deficiency, nuclear type 4A
• Mitochondrial complex V deficiency, nuclear type 7
• Osteopetrosis, autosomal recessive 9
• Pulmonary fibrosis, and/or bone marrow failure, telomere-related, 7
• Pulmonary fibrosis, and/or bone marrow failure, telomere-related, 8
• RECON progeroid syndrome

Changes to the controlled vocabulary for PTMs

New terms for the feature key 'Modified residue' ('MOD_RES' in the flat file):

• L-cysteine coenzyme A disulfide
• Sulfocysteine

Changes in subcellular location controlled vocabulary

New subcellular locations:

• Rhabdomere
• Rhabdomere membrane

UniProt API news

Additional return fields for cross-references in TSV format

The format of our existing UniProtKB return fields for cross-references in a result table consists of the primary identifier of the external resource and, optionally, the UniProt isoform identifier in square brackets. When an entry has several cross-references to the same external resources, these cross-references are separated by a semi-colon.

We have now introduced additional UniProtKB return fields for all cross-references that have additional identifiers or other information. The format of an individual cross-reference is identical to the format used in the UniProtKB text format (with multiple fields being separated by semi-colons). In order to continue to separate multiple cross-references to the same external resource with a semi-colon, each individual cross-reference is enclosed in double quotes.

Example: A0JNW5 Ensembl cross-references

Existing return field xref_ensembl:

ENST00000279907.12 [A0JNW5-1];ENST00000356828.7 [A0JNW5-2];

New return field xref_ensembl_full:

"ENST00000279907.12; ENSP00000279907.7; ENSG00000111647.13. [A0JNW5-1]";"ENST00000356828.7; ENSP00000349285.3; ENSG00000111647.13. [A0JNW5-2]";

Example: A0JNW5 InterPro cross-references

Existing return field xref_interpro:

IPR026728;IPR026854;

New return field xref_interpro_full:

"IPR026728; BLTP3A/B.";"IPR026854; VPS13-like_N."

Headline

Some like it hot

Peppers of the Capsicum genus in the Solanaceae family are native to the Americas and were among the first crops domesticated about 10,000 B.C.E. Interestingly, five different species were independently domesticated in separate regions of the Americas, suggesting a strong interest from humans, possibly because peppers have been used very early in culinary practices and in medicine. Nowadays, peppers are among the most important vegetable and spice crops in the world. Some 3,000 different pepper types are grown worldwide, that differ not only in the color of their fruits or their shape, but more importantly by their heat profile.

Most solanaceous plants protect themselves from herbivores by producing high levels of toxic alkaloids in their leaves. Peppers have evolved another, somewhat more palatable mechanism, one which also aids their propagation; they produce capsaicinoids in their fruit. While not toxic, capsaicinoids bind and activate transient receptor potential vanilloid 1 (or TRPV1) in the mouth, eliciting a heat sensation ferocious enough to discourage mammalian herbivores. Birds, which do not express TRPV1, do not feel the heat; they are attracted to the small red fruit on wild plants and eat them, thereby disseminating their seeds.

The first step of the biosynthetic pathway of capsaicinoids is the synthesis of vanillin from phenylalanine via the phenylpropanoid pathway. Vanillin can be converted to vanillylamine by the pAMT enzyme, also called VAMT. Vanillylamine then undergoes condensation with a branched fatty acid, catalyzed by PUN1. Any variations in the chemical structure of the capsaicinoids, mainly linked to the structure of the acyl moieties attached to the benzene ring of vanillylamine, change our perception not only of the heat intensity, but more generally the heat profile with its myriad of sensations (irritating, mellow-warming, sharp, developing quickly, receding rapidly, lasting hours, etc.)

However, vanillin can also be converted to vanillyl alcohol. The enzyme catalyzing this reaction has long been elusive. It has been recently identified by Sano et al. as cinnamyl alcohol dehydrogenase 1 (or CAD1), an enzyme well-known to plant biologists, because it is essential for the synthesis of lignin, a major cell wall component. Vanillyl alcohol is also a substrate for PUN1. In this case, the condensation with fatty acids produces capsinoids. These are structurally similar to capsaicinoids, except that they have an ester bond instead of an amide bond between the aromatic ring and the branched fatty acid. This small difference makes them mild. The ratio between capsaicinoids and capsinoids determines capsicum pungency. Low-pungent peppers contain a higher content of capsinoids with small amounts of capsaicinoids. Hence the conversion of vanillin into either vanillylamine or vanillyl alcohol is instrumental to determine spiciness.

Whether you like it hot or not, you may enjoy looking at our brand new UniProtKB/Swiss-Prot entries for capsicum enzymes involved in the biosynthetic pathway of capsaicinoids/capsinoids, pAMT, CAD1 and PUN1, which are publicly available as of this release.

UniProtKB news

Change of the cross-references to TAIR

We have modified our cross-references to the TAIR database, and now use the TAIR locus name as the resource identifier, and present the primary gene symbol in an additional field.

Text format

Example: Q8GW48

Previous format:

DR   TAIR; locus:1005716315; AT4G15802.

New format:

DR   TAIR; AT4G15802; HSBP.

XML format

Example: Q8GW48

Previous format:

<dbReference type="TAIR" id="locus:1005716315">
  <property type="gene designation" value="AT4G15802"/>
</dbReference>

New format:

<dbReference type="TAIR" id="AT4G15802">
  <property type="gene designation" value="HSBP"/>
</dbReference>

RDF format

Example: Q8GW48

Previous format:

uniprot:Q8GW48
  rdfs:seeAlso <http://purl.uniprot.org/tair/locus:1005716315> .
<http://purl.uniprot.org/tair/locus:1005716315>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/TAIR> ;
  rdfs:comment "AT4G15802" .

New format:

uniprot:Q8GW48
  rdfs:seeAlso <http://purl.uniprot.org/tair/AT4G15802> .
<http://purl.uniprot.org/tair/AT4G15802>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/TAIR> ;
  rdfs:comment "HSBP" .

Change of the cross-references to TIGRFAMs: replaced by NCBIfam

We have updated our cross-references to reflect the transfer of the TIGRFAMs database to the National Center for Biotechnology Information (NCBI), which now holds the Creative Commons license to this data and is responsible for maintaining and distributing this intellectual property. Following their transfer to NCBI, TIGRFAMs models are now part of a larger HMM collection, NCBIfam, a collection of HMMs built by NCBI curators. All UniProtKB entries cross-referenced to NCBIfam can be found here.

Change of evidence code for the ProtNLM method

The April 2023 release of the ECO ontology introduced several new terms, including ECO:0008006 - "deep learning method evidence used in automatic assertion". This ECO term accurately describes the ProtNLM method, and we have therefore replaced the formerly used ECO:0000256 term by ECO:0008006 for predictions generated by the ProtNLM method.

Changes to the controlled vocabulary of human diseases

New diseases:

• Amyotrophic lateral sclerosis 27, juvenile
• Autoinflammation with pulmonary and cutaneous vasculitis
• Basal cell nevus syndrome 2
• C1q deficiency 2
• C1q deficiency 3
• Ciliary dyskinesia, primary, 50
• Cone-rod dystrophy 24
• Congenital heart defects, multiple types, 9
• Congenital myopathy 10B, mild variant
• Congenital myopathy 2B, severe infantile, autosomal recessive
• Congenital myopathy 2C, severe infantile, autosomal dominant
• Congenital myopathy 20
• Congenital myopathy 21 with early respiratory failure.
• Congenital myopathy 22A, classic
• Congenital myopathy 22B, severe fetal
• Cortical dysplasia, complex, with other brain malformations 12
• Deafness, autosomal dominant, 89.
• Developmental and epileptic encephalopathy 31B
• Diarrhea 13
• Epidermolytic hyperkeratosis 2
• Hatipoglu immunodeficiency syndrome
• Hematuria, benign familial, 2
• Immunodeficiency 109 with lymphoproliferation
• Intellectual developmental disorder, autosomal dominant 71, with behavioral abnormalities
• Intellectual developmental disorder, X-linked 111
• Leukodystrophy, hypomyelinating, 26, with chondrodysplasia
• Leukoencephalopathy with vanishing white matter 2
• Leukoencephalopathy with vanishing white matter 3
• Leukoencephalopathy with vanishing white matter 4
• Leukoencephalopathy with vanishing white matter 5
• Macular dystrophy, retinal, 5
• Mitochondrial complex IV deficiency, nuclear type 23
• Mitochondrial trifunctional protein deficiency 2
• Myopathy, sarcoplasmic body
• Neurodegeneration and seizures due to copper transport defect
• Neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities
• Neurodevelopmental disorder with absent speech and movement and behavioral abnormalities
• Neurodevelopmental disorder with language delay and behavioral abnormalities, with or without seizures
• Neurodevelopmental disorder with microcephaly and speech delay, with or without brain abnormalities
• Neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum
• Neurooculorenal syndrome
• Nystagmus 8, congenital, autosomal recessive
• Oocyte/zygote/embryo maturation arrest 14
• Oocyte/zygote/embryo maturation arrest 17
• Oocyte/zygote/embryo maturation arrest 18
• Oocyte/zygote/embryo maturation arrest 19
• Pituitary hormone deficiency, combined or isolated, 8
• Premature ovarian failure 21
• Prolonged electroretinal response suppression 2
• Retinitis pigmentosa 65
• Spastic paraplegia 70, autosomal recessive
• Spermatogenic failure, X-linked, 5
• Spermatogenic failure, X-linked, 6
• Spermatogenic failure, X-linked, 7
• Spermatogenic failure 81
• Spermatogenic failure 82
• Spermatogenic failure 83

Modified diseases:

• Basal cell nevus syndrome -> Basal cell nevus syndrome 1
• Complement component C1q deficiency -> C1q deficiency 1
• Developmental and epileptic encephalopathy 31 -> Developmental and epileptic encephalopathy 31A
• HDS10 mitochondrial disease -> HSD10 mitochondrial disease
• Hematuria, benign familial -> Hematuria, benign familial, 1
• Immunodeficiency 14A, autosomal dominant -> Immunodeficiency 14A with lymphoproliferation, autosomal dominant
• Immunodeficiency 36 -> Immunodeficiency 36 with lymphoproliferation
• Immunodeficiency 64 -> Immunodeficiency 64 with lymphoproliferation
• Immunodeficiency 72 with autoinflammation -> Immunodeficiency 72 with autoinflammation and lymphoproliferation
• Immunodeficiency 75 -> Immunodeficiency 75 with lymphoproliferation
• Immunodeficiency 8 -> Immunodeficiency 8 with lymphoproliferation
• Intellectual developmental disorder, autosomal dominant 13 -> Cortical dysplasia, complex, with other brain malformations 13
• Leukodystrophy with vanishing white matter -> Leukoencephalopathy with vanishing white matter 1
• Mitochondrial trifunctional protein deficiency -> Mitochondrial trifunctional protein deficiency 1
• Mucocutaneous ulceration, chronic -> Autoinflammatory disease, familial, Behcet-like 3
• Myopathy, congenital, Bailey-Bloch -> Congenital myopathy 13
• Myopathy, congenital, Compton-North -> Congenital myopathy 12
• Myopathy, congenital, non-progressive -> Congenital myopathy 11
• Myopathy, congenital, progressive, with scoliosis -> Congenital myopathy 19
• Myopathy, congenital, with diaphragmatic defects, respiratory insufficiency, and dysmorphic facies -> Congenital myopathy 17
• Myopathy, congenital, with fast-twitch type II fiber atrophy -> Congenital myopathy 14
• Myopathy, congenital, with fiber-type disproportion -> Congenital myopathy 4A, autosomal dominant
• Myopathy, congenital, with neonatal respiratory insufficiency -> Congenital myopathy 15
• Myopathy, congenital, with respiratory insufficiency and bone fractures -> Congenital myopathy 9A
• Myopathy, congenital, with structured cores and Z-line abnormalities -> Congenital myopathy 8
• Myopathy, congenital, with tremor -> Congenital myopathy 16
• Myopathy, congenital proximal, with minicore lesions -> Congenital myopathy 9B, proximal, with minicore lesions
• Myopathy, early-onset, areflexia, respiratory distress, and dysphagia -> Congenital myopathy 10A, severe variant
• Myopathy, myosin storage, autosomal dominant -> Congenital myopathy 7A, myosin storage, autosomal dominant
• Myopathy, myosin storage, autosomal recessive -> Congenital myopathy 7B, myosin storage, autosomal recessive
• Myopathy, proximal, with ophthalmoplegia -> Congenital myopathy 6 with ophthalmoplegia
• Nemaline myopathy 1 -> Congenital myopathy 4B, autosomal recessive
• Nemaline myopathy 3 -> Congenital myopathy 2A, typical, autosomal dominant
• Nystagmus congenital X-linked 1 -> Nystagmus 1, congenital, X-linked
• Nystagmus congenital X-linked 6 -> Nystagmus 6, congenital, X-linked
• Oocyte maturation defect 1 -> Oocyte/zygote/embryo maturation arrest 1
• Oocyte maturation defect 2 -> Oocyte/zygote/embryo maturation arrest 2
• Oocyte maturation defect 3 -> Oocyte/zygote/embryo maturation arrest 3
• Oocyte maturation defect 4 -> Oocyte/zygote/embryo maturation arrest 4
• Oocyte maturation defect 5 -> Oocyte/zygote/embryo maturation arrest 5
• Oocyte maturation defect 6 -> Oocyte/zygote/embryo maturation arrest 6
• Oocyte maturation defect 7 -> Oocyte/zygote/embryo maturation arrest 7
• Oocyte maturation defect 8 -> Oocyte/zygote/embryo maturation arrest 8
• Oocyte maturation defect 9 -> Oocyte/zygote/embryo maturation arrest 9
• Oocyte maturation defect 10 -> Oocyte/zygote/embryo maturation arrest 10
• Oocyte maturation defect 11 -> Oocyte/zygote/embryo maturation arrest 11
• Oocyte maturation defect 12 -> Oocyte/zygote/embryo maturation arrest 12
• Oocyte maturation defect 13 -> Oocyte/zygote/embryo maturation arrest 13
• Preimplantation embryonic lethality 1 -> Oocyte/zygote/embryo maturation arrest 15
• Preimplantation embryonic lethality 2 -> Oocyte/zygote/embryo maturation arrest 16
• Prolonged electroretinal response suppression -> Prolonged electroretinal response suppression 1
• Rigid spine muscular dystrophy 1 -> Congenital myopathy 3 with rigid spine
• Salih myopathy -> Congenital myopathy 5 with cardiomyopathy
• T-cell immunodeficiency, recurrent infections, and autoimmunity with or without cardiac malformations -> Immunodeficiency 110 with lymphoproliferation

Deleted diseases:

• Arrhythmogenic right ventricular dysplasia, familial, 2
• Asperger syndrome, X-linked, 1
• Asperger syndrome, X-linked, 2
• Atrioventricular septal defect 3
• Cap myopathy 1
• Myopathy, actin, congenital, with excess of thin myofilaments
• Scapuloperoneal myopathy MYH7-related
• Spheroid body myopathy

Changes to the controlled vocabulary for PTMs

New terms for the feature key 'Modified residue' ('MOD_RES' in the flat file):

• N-methylaspartate
• N-methylhistidine

UniProt website news

Following the SARS-CoV-2 outbreak in 2020, UniProt published all SARS-CoV-2, SARS and COVID-19 related human protein entries in a pre-release COVID-19 website portal and FTP directory for rapid dissemination of the knowledge about this virus and the COVID-19 disease. With this release, both services have been decommissioned.

Headline

The fair price of an (ant) lunch

Ants live everywhere, on all continents except Antarctica, and they represent the largest number of individual organisms on our planet. Their abundance and nutritional value make them an interesting source of food for many different birds, spiders, mammals, lizards, toads, etc. Some animals feed opportunistically on solitary workers, but others attack colonies to feed on the brood (eggs, larvae, and pupae) and hence could represent a threat for ant species survival. This is the case for giant (15-30 mm body length) red bull ants (Myrmecia gulosa), whose colonies seem to be particularly appreciated by the Australian short-beaked echidna (Tachyglossus aculeatus), an ant-eating monotreme.

Like most ants, giant red bull ants are venomous and can cause extremely painful reactions that last for days. Their venom contains amphipathic peptides, called aculeatoxins, that are capable of activating mammalian sensory neurons, and also a unique cysteine-rich peptide called MIITX2-Mg1a (or Mg1a), which is unrelated to the aculeatoxins and whose function was unknown until recently. Mg1a is the major component of M. gulosa venom. It is predicted to adopt an epidermal growth factor (EGF)-like fold and sequence analysis revealed high sequence similarity to EGF-like peptides. Surprisingly the highest similarity scores were not obtained for insect EGF-like hormones, but for marsupial ones, suggesting that the natural target of Mg1a is not the endogenous EGF receptor (EGFR) but a vertebrate one, possibly that of a mammalian predator. When tested in human cells, Mg1a appeared to be a potent ligand of EGFR with an activity comparable to that of human EGF. Mg1a presence in the venom of M. gulosa may reflect its evolution as a defensive weapon, but then what effect could it have on a vertebrate predator? Shallow intraplantar injection of Mg1a in mice did not cause spontaneous nocifensive behavior, but 2 to 4 hours after injection mice developed hypersensitivity, showing a decreased threshold in paw-withdrawal in response to both mechanical and thermal stimuli. This effect lasted several days. The advantages for the ants of such a delayed effect are not obvious. Possibly the long-lasting hypersensitivity may reduce the duration of the attack, discourage future attacks, or enhance the algesic actions of subsequent exposure to other pain-causing venom peptides.

This is not the first example of biological mimicry, where one organism gains a selective advantage by mimicking an aspect of another organism. Cone snails mimic fish insulin in their venom gland. When hunting, they release venom insulin, causing hypoglycemia and consequently knockdown of their prey, facilitating their capture. However, there is more to this study than just a very elegant discovery of convergent evolution. It also shows the importance of EGFR signaling in mammalian pain, an aspect of EGF function that previously had not receive much attention. EGF is mostly known for its role in wound healing. Following an injury, high concentrations of EGF are released at the wound site where they serve a critical role in wound healing, but they may also sensitize sensory neurons innervating the site of injury. The resulting hypersensitivity may ensure its protection during the healing process. In a very different setting, the involvement of EGF in pain has also been observed. EGFR inhibitors, such as erlotinib, are used in anti-cancer therapy to slow tumor growth. In this context, clinical trials reported that a significant proportion of patients experienced pain relief following treatment. We are still far from the production of new generation pain killers, but by unveiling a new signaling pathway in pain, this study paves the way for future drug developments.

As of this release, the newly annotated Mg1a toxin is publicly available in UniProtKB/Swiss-Prot.

UniProtKB news

Changes to the controlled vocabulary of human diseases

New diseases:

• Cardiomyopathy, dilated, 1OO
• Cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies
• Cataract 50 with or without glaucoma
• Cone-rod dystrophy 23
• Congenital myopathy 18
• Deafness, autosomal dominant, 86
• Deafness, autosomal dominant, 87
• Deafness, autosomal dominant, 88
• Deafness, autosomal recessive, 120
• Developmental delay with hypotonia, myopathy, and brain abnormalities
• Episodic kinesigenic dyskinesia 3
• Hydrocephalus, congenital, 5
• Intellectual developmental disorder, autosomal recessive 78
• Joint contractures, osteochondromas, and B-cell lymphoma
• Leukodystrophy, hypomyelinating, 25
• Lymphatic malformation 13
• Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures
• Neurodevelopmental disorder with poor growth and behavioral abnormalities
• Respiratory infections, recurrent, and failure to thrive with or without diarrhea
• Rhabdomyolysis 1
• Short QT syndrome 7

Modified diseases:

• Cardiomyopathy, dilated 1A -> Cardiomyopathy, dilated, 1A
• Cardiomyopathy, dilated 1AA, with or without left ventricular non-compaction -> Cardiomyopathy, dilated, 1AA, with or without left ventricular non-compaction
• Cardiomyopathy, dilated 1BB -> Cardiomyopathy, dilated, 1BB
• Cardiomyopathy, dilated 1C, with or without left ventricular non-compaction -> Cardiomyopathy, dilated, 1C, with or without left ventricular non-compaction
• Cardiomyopathy, dilated 1CC -> Cardiomyopathy, dilated, 1CC
• Cardiomyopathy, dilated 1D -> Cardiomyopathy, dilated, 1D
• Cardiomyopathy, dilated 1DD -> Cardiomyopathy, dilated, 1DD
• Cardiomyopathy, dilated 1E -> Cardiomyopathy, dilated, 1E
• Cardiomyopathy, dilated 1EE -> Cardiomyopathy, dilated, 1EE
• Cardiomyopathy, dilated 1FF -> Cardiomyopathy, dilated, 1FF
• Cardiomyopathy, dilated 1G -> Cardiomyopathy, dilated, 1G
• Cardiomyopathy, dilated 1GG -> Cardiomyopathy, dilated, 1GG
• Cardiomyopathy, dilated 1HH -> Cardiomyopathy, dilated, 1HH
• Cardiomyopathy, dilated 1I -> Cardiomyopathy, dilated, 1I
• Cardiomyopathy, dilated 1II -> Cardiomyopathy, dilated, 1II
• Cardiomyopathy, dilated 1J -> Cardiomyopathy, dilated, 1J
• Cardiomyopathy, dilated 1JJ -> Cardiomyopathy, dilated, 1JJ
• Cardiomyopathy, dilated 1KK -> Cardiomyopathy, dilated, 1KK
• Cardiomyopathy, dilated 1L -> Cardiomyopathy, dilated, 1L
• Cardiomyopathy, dilated 1LL -> Cardiomyopathy, dilated, 1LL
• Cardiomyopathy, dilated 1M -> Cardiomyopathy, dilated, 1M
• Cardiomyopathy, dilated 1MM -> Cardiomyopathy, dilated, 1MM
• Cardiomyopathy, dilated 1NN -> Cardiomyopathy, dilated, 1NN
• Cardiomyopathy, dilated 1O -> Cardiomyopathy, dilated, 1O
• Cardiomyopathy, dilated 1P -> Cardiomyopathy, dilated, 1P
• Cardiomyopathy, dilated 1R -> Cardiomyopathy, dilated, 1R
• Cardiomyopathy, dilated 1S -> Cardiomyopathy, dilated, 1S
• Cardiomyopathy, dilated 1U -> Cardiomyopathy, dilated, 1U
• Cardiomyopathy, dilated 1V -> Cardiomyopathy, dilated, 1V
• Cardiomyopathy, dilated 1W -> Cardiomyopathy, dilated, 1W
• Cardiomyopathy, dilated 1X -> Cardiomyopathy, dilated, 1X
• Cardiomyopathy, dilated 1Y -> Cardiomyopathy, dilated, 1Y
• Cardiomyopathy, dilated 1Z -> Cardiomyopathy, dilated, 1Z
• Cardiomyopathy, dilated 2A -> Cardiomyopathy, dilated, 2A
• Cardiomyopathy, dilated 2B -> Cardiomyopathy, dilated, 2B
• Cardiomyopathy, dilated 2C -> Cardiomyopathy, dilated, 2C
• Cardiomyopathy, dilated 2D -> Cardiomyopathy, dilated, 2D
• Cardiomyopathy, dilated 2E -> Cardiomyopathy, dilated, 2E
• Cardiomyopathy, dilated 2F -> Cardiomyopathy, dilated, 2F
• Cardiomyopathy, dilated 2G -> Cardiomyopathy, dilated, 2G
• Cardiomyopathy, dilated 2H -> Cardiomyopathy, dilated, 2H
• Cardiomyopathy, dilated, X-linked 3B -> Cardiomyopathy, dilated, 3B
• Cardiomyopathy, familial hypertrophic 1 -> Cardiomyopathy, familial hypertrophic, 1
• Cardiomyopathy, familial hypertrophic 10 -> Cardiomyopathy, familial hypertrophic, 10
• Cardiomyopathy, familial hypertrophic 11 -> Cardiomyopathy, familial hypertrophic, 11
• Cardiomyopathy, familial hypertrophic 12 -> Cardiomyopathy, familial hypertrophic, 12
• Cardiomyopathy, familial hypertrophic 13 -> Cardiomyopathy, familial hypertrophic, 13
• Cardiomyopathy, familial hypertrophic 14 -> Cardiomyopathy, familial hypertrophic, 14
• Cardiomyopathy, familial hypertrophic 15 -> Cardiomyopathy, familial hypertrophic, 15
• Cardiomyopathy, familial hypertrophic 16 -> Cardiomyopathy, familial hypertrophic, 16
• Cardiomyopathy, familial hypertrophic 17 -> Cardiomyopathy, familial hypertrophic, 17
• Cardiomyopathy, familial hypertrophic 18 -> Cardiomyopathy, familial hypertrophic, 18
• Cardiomyopathy, familial hypertrophic 2 -> Cardiomyopathy, familial hypertrophic, 2
• Cardiomyopathy, familial hypertrophic 20 -> Cardiomyopathy, familial hypertrophic, 20
• Cardiomyopathy, familial hypertrophic 22 -> Cardiomyopathy, familial hypertrophic, 22
• Cardiomyopathy, familial hypertrophic 23, with or without left ventricular non-compaction -> Cardiomyopathy, familial hypertrophic, 23, with or without left ventricular non-compaction
• Cardiomyopathy, familial hypertrophic 24 -> Cardiomyopathy, familial hypertrophic, 24
• Cardiomyopathy, familial hypertrophic 25 -> Cardiomyopathy, familial hypertrophic, 25
• Cardiomyopathy, familial hypertrophic 26 -> Cardiomyopathy, familial hypertrophic, 26
• Cardiomyopathy, familial hypertrophic 27 -> Cardiomyopathy, familial hypertrophic, 27
• Cardiomyopathy, familial hypertrophic 28 -> Cardiomyopathy, familial hypertrophic, 28
• Cardiomyopathy, familial hypertrophic 3 -> Cardiomyopathy, familial hypertrophic, 3
• Cardiomyopathy, familial hypertrophic 4 -> Cardiomyopathy, familial hypertrophic, 4
• Cardiomyopathy, familial hypertrophic 6 -> Cardiomyopathy, familial hypertrophic, 6
• Cardiomyopathy, familial hypertrophic 7 -> Cardiomyopathy, familial hypertrophic, 7
• Cardiomyopathy, familial hypertrophic 8 -> Cardiomyopathy, familial hypertrophic, 8
• Cardiomyopathy, familial hypertrophic 9 -> Cardiomyopathy, familial hypertrophic, 9
• Central core disease of muscle -> Congenital myopathy 1A, autosomal dominant, with susceptibility to malignant hyperthermia
• Coffin-Siris syndrome 9 -> Intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism
• Epidermolysis bullosa simplex 6, generalized, with scarring and hair loss -> Epidermolysis bullosa simplex 6, generalized intermediate, with or without cardiomyopathy
• Familial hyperinsulinemic hypoglycemia 1 -> Hyperinsulinemic hypoglycemia, familial, 1
• Familial hyperinsulinemic hypoglycemia 2 -> Hyperinsulinemic hypoglycemia, familial, 2
• Familial hyperinsulinemic hypoglycemia 3 -> Hyperinsulinemic hypoglycemia, familial, 3
• Familial hyperinsulinemic hypoglycemia 4 -> Hyperinsulinemic hypoglycemia, familial, 4
• Familial hyperinsulinemic hypoglycemia 5 -> Hyperinsulinemic hypoglycemia, familial, 5
• Familial hyperinsulinemic hypoglycemia 6 -> Hyperinsulinemic hypoglycemia, familial, 6
• Familial hyperinsulinemic hypoglycemia 7 -> Hyperinsulinemic hypoglycemia, familial, 7
• Hydrocephalus, congenital communicating, 1 -> Hydrocephalus, congenital, 4
• Hydrocephalus due to stenosis of the aqueduct of Sylvius -> Hydrocephalus, congenital, X-linked
• Multiminicore disease with external ophthalmoplegia -> Congenital myopathy 1B, autosomal recessive
• Neurodevelopmental disorder with severe motor impairment and absent language -> Neurodevelopmental disorder with variable motor and language impairment
• Retinitis pigmentosa and sinorespiratory infections with or without deafness -> Retinitis pigmentosa, X-linked, and sinorespiratory infections with or without deafness
• Sickle cell anemia -> Sickle cell disease

Changes to the controlled vocabulary for PTMs

New terms for the feature key 'Glycosylation' ('CARBOHYD' in the flat file):

• O-alpha-linked (D-glycero-D-manno-heptose) serine
• O-alpha-linked (glycero-D-manno-heptose) serine
• O-alpha-linked (glycero-D-manno-heptose) threonine

New term for the feature key 'Modified residue' ('MOD_RES' in the flat file):

• N-methylvaline
• N-methylthreonine

Changes in subcellular location controlled vocabulary

Modified subcellular locations:

• Gas vesicle membrane -> Gas vesicle shell

Headline

Levering the DNA

During the process of genetic recombination, two double-stranded DNA (dsDNA) molecules are separated into four strands, enabling exchange of segments of genetic information. These amazing four-stranded branched DNA structures are called Holliday junctions (HJs). HJs are also formed during DNA double-strand break repair and replication fork rescue, and their resolution is essential for all cellular life forms. The mobile HJ DNA heteroduplexes undergo ATP-dependent branch migration; think of them as a cruciform structure that moves along DNA. The bacterial RuvABC proteins, named after their property to confer cellular resistance to UV light, have been known for years to be instrumental in one of the pathways involved in the resolution of HJs. RuvC is a Holliday junction resolvase, an endonuclease, that acts at specific sequences. At these sites, RuvC makes single-stranded nicks across the cruciform at symmetrical sites, allowing resolution of the 4-branch DNA into 2 double-stranded DNA strands. To find the appropriate cleavage site, the HJ junction undergoes branch migration and RuvAB is essential for the migration.

Recent work by the group of Thomas Marlovits has shed new light on the mechanism by which branch migration occurs. They used time-resolved cryo-electron microscopy to solve distinct intermediates in the assembly and processing of the bacterial HJ. A pair of RuvA homotetramers sandwich and slightly flatten the center of the double-stranded cruciform HJ DNA, with the (potential) HJ resolution site in the middle of the complex. RuvB assembles into an asymmetric hexameric ring with a central pore surrounding DNA. Two RuvB homohexamers assemble on opposite strands of dsDNA as it exits the RuvA-HJ core. The C-terminal domain of 2 RuvA subunits binds 2 adjacent RuvB subunits. RuvB is a ring-shaped AAA+ ATPase motor and coordinated movements among the 4 DNA-disengaged subunits (called the converter) stimulate ATP hydrolysis, nucleotide exchange and ultimately branch migration by these subunits. The converter subunits are trapped on the DNA by their contact with RuvA, thus the energy released during ATP hydrolysis is converted into a lever motion, where RuvA anchors RuvB which then lifts and pulls 2 nucleotides of DNA through the center of the homohexamer. At the same time the complex rotates with the DNA, 60° at a time. When one ATP cycle is over the RuvA subunits disengage from RuvB and bind to the next subunits of the RuvB hexamer; the cycle recommences. Both RuvB homohexamers pull DNA, allowing a continual search for the RuvC recognition sequence. How RuvC scans the DNA is unknown, although it is assumed it displaces one of the RuvA tetramers to resolve the HJ DNA.

The data suggest that the majority of ring-shaped AAA+ motors may function as molecular levers, converting protein conformational changes into lift activity of their central pores, which subsequently facilitates substrate (in this case DNA) translocation. Elucidation of this mechanism will allow other motors to be re-examined and may lead to the design of compounds that target specific states of the motor.

RuvA, RuvB and RuvC have been updated and are available in UniProtKB/Swiss-Prot.

UniProtKB news

Changes in prokaryotic taxonomy

In release 2023_02, prokaryotic taxonomy will be changed in accordance with alterations that have occurred in the NCBI taxonomy database. These changes are due to inclusion of the rank phylum in the International Code of Nomenclature for Prokaryotes (INCP), and are based on a recommendation made by Oren and Garrity, 2021. Examples of the changes include Firmicutes to Bacillota, Crenarchaeota to Thermoproteota, and Proteobacteria to Pseudomonadota. A full list of the phylum name changes is here.

Changes to the controlled vocabulary of human diseases

New diseases:

• Atelis syndrome 1
• Atelis syndrome 2
• Branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome
• Cardiomyopathy, dilated 2H
• Charcot-Marie-Tooth disease, demyelinating, 1J
• Ciliary dyskinesia, primary, 49, without situs inversus
• Combined oxidative phosphorylation deficiency 56
• Combined oxidative phosphorylation deficiency 57
• Congenital disorder of glycosylation 2Y
• Congenital disorder of glycosylation 2Z
• Cortical dysplasia, complex, with other brain malformations 11
• Deafness, autosomal dominant, 85
• Developmental and epileptic encephalopathy 108
• Developmental and epileptic encephalopathy 109
• Developmental and epileptic encephalopathy 110
• Developmental delay, language impairment, and ocular abnormalities
• Developmental delay with variable intellectual disability and dysmorphic facies
• Dyskeratosis congenita, autosomal recessive, 8
• Epilepsy, X-linked 2, with or without impaired intellectual development and dysmorphic features
• Hyperinsulinemic hypoglycemia, familial, 8
• Hypermetabolism due to uncoupled mitochondrial oxidative phosphorylation 2
• Hypomagnesemia 7, renal, with or without dilated cardiomyopathy
• Hypotrichosis 15
• Ichthyosis, annular epidermolytic, 2
• Ichthyosis histrix, Lambert type
• Inflammatory poikiloderma with hair abnormalities and acral keratoses
• Intellectual developmental disorder, autosomal dominant 70
• Intellectual developmental disorder, X-linked 110
• Iron overload
• Lacrimo-auriculo-dento-digital syndrome 2
• Lacrimo-auriculo-dento-digital syndrome 3
• Microcephaly 30, primary, autosomal recessive
• Mitochondrial complex I deficiency, nuclear type 39
• Mitochondrial complex III deficiency, nuclear type 11
• Mosaic variegated aneuploidy syndrome 4
• Mosaic variegated aneuploidy syndrome 7 with inflammation and tumor predisposition
• Muscular dystrophy, congenital, with or without seizures
• Myopathy, congenital, with neonatal respiratory insufficiency
• Myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis
• Neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia
• Neurodevelopmental disorder with gait disturbance, dysmorphic facies, and behavioral abnormalities, X-linked
• Neurodevelopmental disorder with growth retardation, dysmorphic facies, and corpus callosum abnormalities
• Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skin abnormalities
• Neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies
• Neurodevelopmental disorder with speech impairment and with or without seizures
• Obesity and hypopigmentation
• Oocyte maturation defect 13
• Pseudohypoaldosteronism 1B2, autosomal recessive
• Pseudohypoaldosteronism 1B3, autosomal recessive
• Rabin-Pappas syndrome
• Retinitis pigmentosa 96
• Spastic paraplegia 79A, autosomal dominant, with ataxia
• Spastic paraplegia 88, autosomal dominant
• Spermatogenic failure 78
• Spermatogenic failure 79
• Spermatogenic failure 80
• Spinocerebellar ataxia 27B, late-onset
• Spinocerebellar ataxia 50
• Tooth agenesis, selective, 10

Modified diseases:

• Alacrima, achalasia, and intellectual disability syndrome -> Alacrima, achalasia, and impaired intellectual development syndrome
• Alpha-thalassemia/intellectual disability syndrome, X-linked -> Alpha-thalassemia/impaired intellectual development syndrome, X-linked
• Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1 -> Cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome 1
• Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 2 -> Cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome
• Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 3 -> Cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome 3
• Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4 -> Cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome 4
• Charcot-Marie-Tooth disease, dominant, intermediate type, B -> Charcot-Marie-Tooth disease, dominant intermediate B
• Charcot-Marie-Tooth disease, dominant, intermediate type, C -> Charcot-Marie-Tooth disease, dominant intermediate C
• Charcot-Marie-Tooth disease, dominant, intermediate type, D -> Charcot-Marie-Tooth disease, dominant intermediate D
• Charcot-Marie-Tooth disease, dominant, intermediate type, E -> Charcot-Marie-Tooth disease, dominant intermediate E
• Charcot-Marie-Tooth disease, dominant, intermediate type, F -> Charcot-Marie-Tooth disease, dominant intermediate F
• Charcot-Marie-Tooth disease, recessive, intermediate type, A -> Charcot-Marie-Tooth disease, recessive intermediate A
• Charcot-Marie-Tooth disease, recessive, intermediate type, B -> Charcot-Marie-Tooth disease, recessive intermediate B
• Charcot-Marie-Tooth disease, recessive, intermediate type, C -> Charcot-Marie-Tooth disease, recessive intermediate C
• Charcot-Marie-Tooth disease, recessive, intermediate type, D -> Charcot-Marie-Tooth disease, recessive intermediate D
• Charcot-Marie-Tooth disease 1A -> Charcot-Marie-Tooth disease, demyelinating, 1A
• Charcot-Marie-Tooth disease 1B -> Charcot-Marie-Tooth disease, demyelinating, 1B
• Charcot-Marie-Tooth disease 1C -> Charcot-Marie-Tooth disease, demyelinating, 1C
• Charcot-Marie-Tooth disease 1D -> Charcot-Marie-Tooth disease, demyelinating, 1D
• Charcot-Marie-Tooth disease 1E -> Charcot-Marie-Tooth disease, demyelinating, 1E
• Charcot-Marie-Tooth disease 1F -> Charcot-Marie-Tooth disease, demyelinating, 1F
• Charcot-Marie-Tooth disease 2A1 -> Charcot-Marie-Tooth disease, axonal, 2A1
• Charcot-Marie-Tooth disease 2A2A -> Charcot-Marie-Tooth disease, axonal, 2A2A
• Charcot-Marie-Tooth disease 2A2B -> Charcot-Marie-Tooth disease, axonal, 2A2B
• Charcot-Marie-Tooth disease 2B -> Charcot-Marie-Tooth disease, axonal, 2B
• Charcot-Marie-Tooth disease 2B1 -> Charcot-Marie-Tooth disease, axonal, 2B1
• Charcot-Marie-Tooth disease 2B2 -> Charcot-Marie-Tooth disease, axonal, 2B2
• Charcot-Marie-Tooth disease 2C -> Charcot-Marie-Tooth disease, axonal, 2C
• Charcot-Marie-Tooth disease 2CC -> Charcot-Marie-Tooth disease, axonal, 2CC
• Charcot-Marie-Tooth disease 2D -> Charcot-Marie-Tooth disease, axonal, 2D
• Charcot-Marie-Tooth disease 2DD -> Charcot-Marie-Tooth disease, axonal, 2DD
• Charcot-Marie-Tooth disease 2E -> Charcot-Marie-Tooth disease, axonal, 2E
• Charcot-Marie-Tooth disease 2F -> Charcot-Marie-Tooth disease, axonal, 2F
• Charcot-Marie-Tooth disease 2FF -> Charcot-Marie-Tooth disease, axonal, 2FF
• Charcot-Marie-Tooth disease 2HH -> Charcot-Marie-Tooth disease, axonal, 2HH
• Charcot-Marie-Tooth disease 2I -> Charcot-Marie-Tooth disease, axonal, 2I
• Charcot-Marie-Tooth disease 2II -> Charcot-Marie-Tooth disease, axonal, 2II
• Charcot-Marie-Tooth disease 2J -> Charcot-Marie-Tooth disease, axonal, 2J
• Charcot-Marie-Tooth disease 2K -> Charcot-Marie-Tooth disease, axonal, 2K
• Charcot-Marie-Tooth disease 2L -> Charcot-Marie-Tooth disease, axonal, 2L
• Charcot-Marie-Tooth disease 2M -> Charcot-Marie-Tooth disease, axonal, 2M
• Charcot-Marie-Tooth disease 2N -> Charcot-Marie-Tooth disease, axonal, 2N
• Charcot-Marie-Tooth disease 2O -> Charcot-Marie-Tooth disease, axonal, 2O
• Charcot-Marie-Tooth disease 2P -> Charcot-Marie-Tooth disease, axonal, 2P
• Charcot-Marie-Tooth disease 2Q -> Charcot-Marie-Tooth disease, axonal, 2Q
• Charcot-Marie-Tooth disease 2R -> Charcot-Marie-Tooth disease, axonal, 2R
• Charcot-Marie-Tooth disease 2S -> Charcot-Marie-Tooth disease, axonal, 2S
• Charcot-Marie-Tooth disease 2T -> Charcot-Marie-Tooth disease, axonal, 2T
• Charcot-Marie-Tooth disease 2U -> Charcot-Marie-Tooth disease, axonal, 2U
• Charcot-Marie-Tooth disease 2V -> Charcot-Marie-Tooth disease, axonal, 2V
• Charcot-Marie-Tooth disease 2W -> Charcot-Marie-Tooth disease, axonal, 2W
• Charcot-Marie-Tooth disease 2X -> Charcot-Marie-Tooth disease, axonal, 2X
• Charcot-Marie-Tooth disease 2Y -> Charcot-Marie-Tooth disease, axonal, 2Y
• Charcot-Marie-Tooth disease 2Z -> Charcot-Marie-Tooth disease, axonal, 2Z
• Cleft palate, cardiac defects, and intellectual disability -> Cleft palate, cardiac defects, and impaired intellectual development
• Coffin-Siris syndrome 10 -> Intellectual developmental disorder with speech delay and dysmorphic facies
• Coloboma, congenital heart disease, ichthyosiform dermatosis, intellectual disability and ear anomalies syndrome -> Coloboma, congenital heart disease, ichthyosiform dermatosis, impaired intellectual development, and ear anomalies syndrome
• Coloboma, ocular, with or without hearing impairment, cleft lip/palate, and/or intellectual disability -> Coloboma, ocular, with or without hearing impairment, cleft lip/palate, and/or impaired intellectual development
• Deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures syndrome -> Deafness, onychodystrophy, osteodystrophy, impaired intellectual development, and seizures syndrome
• Epilepsy, X-linked, with variable learning disabilities and behavior disorders -> Epilepsy, X-linked 1, with variable learning disabilities and behavior disorders
• Hereditary non-polyposis colorectal cancer 1 -> Lynch syndrome 1
• Hereditary non-polyposis colorectal cancer 2 -> Lynch syndrome 2
• Hereditary non-polyposis colorectal cancer 4 -> Lynch syndrome 4
• Hereditary non-polyposis colorectal cancer 5 -> Lynch syndrome 5
• Hereditary non-polyposis colorectal cancer 8 -> Lynch syndrome 8
• Hyperphosphatasia with intellectual disability syndrome 1 -> Hyperphosphatasia with impaired intellectual development syndrome 1
• Hyperphosphatasia with intellectual disability syndrome 2 -> Hyperphosphatasia with impaired intellectual development syndrome 2
• Hyperphosphatasia with intellectual disability syndrome 3 -> Hyperphosphatasia with impaired intellectual development syndrome 3
• Hyperphosphatasia with intellectual disability syndrome 4 -> Hyperphosphatasia with impaired intellectual development syndrome 4
• Hyperphosphatasia with intellectual disability syndrome 6 -> Hyperphosphatasia with impaired intellectual development syndrome 6
• Hypomagnesemia, seizures, and intellectual disability 1 -> Hypomagnesemia, seizures, and impaired intellectual development 1
• Hypomagnesemia, seizures, and intellectual disability 2 -> Hypomagnesemia, seizures, and impaired intellectual development 2
• Ichthyosis, spastic quadriplegia, and intellectual disability -> Ichthyosis, spastic quadriplegia, and impaired intellectual development
• Ichthyosis annular epidermolytic -> Ichthyosis, annular epidermolytic, 1
• Intellectual disability, anterior maxillary protrusion, and strabismus -> Impaired intellectual development, anterior maxillary protrusion, and strabismus
• Intellectual disability, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma -> MEDNIK syndrome
• Intellectual disability, truncal obesity, retinal dystrophy, and micropenis -> Impaired intellectual development, truncal obesity, retinal dystrophy, and micropenis
• Lacrimo-auriculo-dento-digital syndrome -> Lacrimo-auriculo-dento-digital syndrome 1
• Macular degeneration, X-linked, atrophic -> Macular degeneration, atrophic, X-linked
• Microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability -> Microcephaly with or without chorioretinopathy, lymphedema, or impaired intellectual development
• Microphthalmia, isolated, 3 -> Microphthalmia, syndromic 16
• Mitochondrial complex III deficiency, nuclear 1 -> Mitochondrial complex III deficiency, nuclear type 1
• Mitochondrial complex III deficiency, nuclear 2 -> Mitochondrial complex III deficiency, nuclear type 2
• Mitochondrial complex III deficiency, nuclear 3 -> Mitochondrial complex III deficiency, nuclear type 3
• Mitochondrial complex III deficiency, nuclear 4 -> Mitochondrial complex III deficiency, nuclear type 4
• Mitochondrial complex III deficiency, nuclear 5 -> Mitochondrial complex III deficiency, nuclear type 5
• Mitochondrial complex III deficiency, nuclear 6 -> Mitochondrial complex III deficiency, nuclear type 6
• Mitochondrial complex III deficiency, nuclear 7 -> Mitochondrial complex III deficiency, nuclear type
• Mitochondrial complex III deficiency, nuclear 8 -> Mitochondrial complex III deficiency, nuclear type 8
• Mitochondrial complex III deficiency, nuclear 9 -> Mitochondrial complex III deficiency, nuclear type 9
• Mitochondrial complex III deficiency, nuclear 10 -> Mitochondrial complex III deficiency, nuclear type 10
• Optic atrophy 10 with or without ataxia, intellectual disability, and seizures -> Optic atrophy 10 with or without ataxia, impaired intellectual development, and seizures
• Pseudohypoaldosteronism 1, autosomal recessive -> Pseudohypoaldosteronism 1B1, autosomal recessive
• Renal tubular acidosis, proximal, with ocular abnormalities and intellectual disability -> Renal tubular acidosis, proximal, with ocular abnormalities and impaired intellectual development
• Seizures, sensorineural deafness, ataxia, intellectual disability, and electrolyte imbalance -> Seizures, sensorineural deafness, ataxia, impaired intellectual development, and electrolyte imbalance
• Spastic paraplegia 79, autosomal recessive -> Spastic paraplegia 79B, autosomal recessive
• Spinocerebellar ataxia 27 -> Spinocerebellar ataxia 27A
• Tessadori-van Haaften neurodevelopmental syndrome 1 -> Tessadori-Bicknell-Van Haaften neurodevelopmental syndrome 1
• Tessadori-van Haaften neurodevelopmental syndrome 2 -> Tessadori-Bicknell-Van Haaften neurodevelopmental syndrome 2
• Tessadori-van Haaften neurodevelopmental syndrome 3 -> Tessadori-Bicknell-Van Haaften neurodevelopmental syndrome 3
• Tessadori-van Haaften neurodevelopmental syndrome 4 -> Tessadori-Bicknell-Van Haaften neurodevelopmental syndrome 4

Deleted diseases

• Cortical dysplasia, complex, with other brain malformations 8

Headline

Killing me softly

In order to rapidly get rid of infectious microorganisms our innate immune system relies, among others, on specific intracellular receptors which recognize patterns that are frequently found in pathogens. One of these pattern recognition receptors (PRRs), NLRC4, recognizes many different bacterial pathogens, including Salmonella typhimurium, by sensing bacterial flagellin or structural components of the bacterial type III secretion system that are injected or leaked into the host cell. NLRC4 activation leads to the assembly of inflammasomes, large cytosolic multiprotein complexes, which results in the activation of caspase 1 (CASP1). CASP1 initiates inflammatory responses, including activation of the cytokines IL1B and IL18, and cleavage of gasdermin D (GSDMD). This latter forms pores in the plasma membrane, leading to inflammatory cell death, called pyroptosis, within minutes to hours. At the end of this cascade, the cell is dead. End of story? Well, not really. The activation of inflammasomes does not always lead to pyroptosis, and in certain settings, cells with active inflammasomes and gasdermin pores demonstrate a hypersecretory cytokine phenotype without undergoing cell death. How is this possible?

Yet another aspect of the process was unclear. CASP1 also activates 'apoptotic' caspases, such as CASP3 and CASP7, with CASP3 being the primary apoptotic executioner and CASP7 being considered as an inefficient CASP3 back-up. However, CASP7 pro-apoptotic activity is very weak, if it has any. What then is CASP7's function?

Our understanding of the process made a leap forward thanks to a recent article by Nozaki et al. Using intestinal epithelial cell organoid cultures and transgenic mice, the authors studied S.typhimurium infection. As expected in this setting, NLRC4 activation resulted in CASP1 activation. CASP1 in turn activated GSDMD and CASP7. As expected, GSDMD formed pores at the plasma membrane. The new observation is that CASP7 activated a lysosomal enzyme, sphingomyelin phosphodiesterase, also called ASM or SMPD1, which converts sphingomyelin into ceramide. Sphingomyelin is a major constituent of the plasma membrane in animal cells, allowing the membrane to remain largely flat. The formation of ceramide at the cell surface causes the membrane to naturally invaginate, inducing spontaneous clathrin-independent endocytosis that internalizes GSDMD pores, ensuring local repair of the plasma membrane. But how can cytosolic CASP7 activate a lysosomal protein? The current hypothesis is that GSDMD pores allow a massive influx of calcium, which causes lysosomal exocytosis and delivers pro-SMPD1 to the cell surface. CASP7 could pass from the cytosol through the pores to the extracellular space, where the proteins would meet at the best location for rapid membrane repair.

In the intestinal epithelium, the removal of dying cells proceeds through a unique process called cell extrusion, in order to preserve the integrity of barrier function. During extrusion, the cell fated to die emits the lipid sphingosine-1-phosphate, which causes contraction of an actomyosin ring in the neighboring cells. This contraction acts to squeeze the cell out apically while drawing together neighboring cells and preventing any gaps in the epithelial barrier. In this context, SMPD1-mediated repair of the plasma membrane would delay the rapid pore-driven cell lysis to allow the slower extrusion process to engage.

Interestingly, these findings can be expanded to other cell types and infections. For instance, SMPD1 also mediates the repair of pores made by natural killer cell perforin in hepatocytes infected by Chromobacterium violaceum.

The updated UniProtKB/Swiss-Prot entries for CASP7, SMPD1, and GSDMD are now publicly available.

UniProtKB news

Cross-references to GlyCosmos

Cross-references have been added to GlyCosmos, a portal integrating glycosciences with life sciences.

GlyCosmos is available at https://glycosmos.org/.

The format of the explicit links is:

Resource abbreviation	GlyCosmos
Resource identifier	UniProtKB accession number
Optional information 1	Glycosylation details

Example: P24387

Show all entries having a cross-reference to GlyCosmos.

Text format

Example: P24387

DR   GlyCosmos; P24387; 1 site, 6 glycans.

XML format

Example: P24387

<dbReference type="GlyCosmos" id="P24387">
  <property type="glycosylation" value="1 site, 6 glycans"/>
</dbReference>

RDF format

Example: P24387

uniprot:P24387
  rdfs:seeAlso <http://purl.uniprot.org/glycosmos/P24387> .
<http://purl.uniprot.org/glycosmos/P24387>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/GlyCosmos> ;
  rdfs:comment "1 site, 6 glycans" .

Change to the cross-references to Gene3D

In 2013, The Gene3D database no longer provided names for their signatures. To be consistent with the other family and domain databases, whenever possible, GeneDB cross-references are presented with names for their signatures again.

Example: Q12933

Text format

Example: Q12933

Previous format:

DR   Gene3D; 1.20.5.170; -; 1.
DR   Gene3D; 3.30.40.10; -; 3.

New format:

DR   Gene3D; 1.20.5.170; -; 1.
DR   Gene3D; 3.30.40.10; Zinc/RING finger domain, C3HC4 (zinc finger); 3.

XML format

Example: Q12933

Previous format:

<dbReference type="Gene3D" id="1.20.5.170">
  <property type="match status" value="1"/>
</dbReference>
<dbReference type="Gene3D" id="3.30.40.10">
  <property type="match status" value="3"/>
</dbReference>

New format:

<dbReference type="Gene3D" id="1.20.5.170">
  <property type="match status" value="1"/>
</dbReference>
<dbReference type="Gene3D" id="3.30.40.10">
  <property type="entry name" value="Zinc/RING finger domain, C3HC4 (zinc finger)"/>
  <property type="match status" value="3"/>
</dbReference>

RDF format

Example: Q12933

Previous format:

uniprot:Q12933
 rdfs:seeAlso <http://purl.uniprot.org/gene3d/1.20.5.170> ,
              <http://purl.uniprot.org/gene3d/3.30.40.10> .
<http://purl.uniprot.org/gene3d/1.20.5.170> rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/Gene3D> ;
  up:signatureSequenceMatch <http://purl.uniprot.org/isoforms/Q12933-1#Gene3D_1.20.5.170_match_1> .
<http://purl.uniprot.org/gene3d/3.30.40.10>  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/Gene3D> ;
  up:signatureSequenceMatch <http://purl.uniprot.org/isoforms/Q12933-1#Gene3D_3.30.40.10_match_1> ,
    <http://purl.uniprot.org/isoforms/Q12933-1#Gene3D_3.30.40.10_match_2> ,
    <http://purl.uniprot.org/isoforms/Q12933-1#Gene3D_3.30.40.10_match_3> .

New format:

uniprot:Q12933
 rdfs:seeAlso <http://purl.uniprot.org/gene3d/1.20.5.170> ,
              <http://purl.uniprot.org/gene3d/3.30.40.10> .
<http://purl.uniprot.org/gene3d/1.20.5.170> rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/Gene3D> ;
  up:signatureSequenceMatch <http://purl.uniprot.org/isoforms/Q12933-1#Gene3D_1.20.5.170_match_1> .
<http://purl.uniprot.org/gene3d/3.30.40.10>  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/Gene3D> ;
  rdfs:comment "Zinc/RING finger domain, C3HC4 (zinc finger)" ;
  up:signatureSequenceMatch <http://purl.uniprot.org/isoforms/Q12933-1#Gene3D_3.30.40.10_match_1> ,
    <http://purl.uniprot.org/isoforms/Q12933-1#Gene3D_3.30.40.10_match_2> ,
    <http://purl.uniprot.org/isoforms/Q12933-1#Gene3D_3.30.40.10_match_3> .

Changes to the controlled vocabulary of human diseases

New diseases:

• Amelogenesis imperfecta 1K
• Bent bone dysplasia syndrome 2
• Bone marrow failure and diabetes mellitus syndrome
• Cardiac valvular dysplasia 2
• Charcot-Marie-Tooth disease 2II
• Ciliary dyskinesia, primary, 48, without situs inversus
• Cleidocranial dysplasia 2
• Developmental and epileptic encephalopathy 106
• Developmental and epileptic encephalopathy 107
• Developmental delay, behavioral abnormalities, and neuropsychiatric disorders
• Developmental delay with short stature, dysmorphic facial features, and sparse hair 2
• Diamond-Blackfan anemia 21
• Diaphragmatic hernia 4, with cardiovascular defects
• Dyskeratosis congenita, digenic
• Familial apolipoprotein gene cluster deletion syndrome
• Glioma 7
• Immunodeficiency 108 with autoinflammation
• Intellectual developmental disorder with autism and dysmorphic facies
• Intellectual developmental disorder with ocular anomalies and distinctive facial features
• Intestinal dysmotility syndrome
• Microcephaly 29, primary, autosomal recessive
• Nephrotic syndrome 26
• Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction
• Neurodevelopmental disorder with craniofacial dysmorphism and skeletal defects
• Neurodevelopmental disorder with dysmorphic facies and skeletal and brain abnormalities
• Neurodevelopmental disorder with eye movement abnormalities and ataxia
• Neurodevelopmental disorder with facial dysmorphism, absent language, and pseudo-Pelger-Huet anomaly
• Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures
• Neurodevelopmental disorder with microcephaly, cerebral atrophy, and visual impairment
• Neurodevelopmental disorder with microcephaly, hypotonia, and absent language
• Neurodevelopmental disorder with microcephaly, movement abnormalities, and seizures
• Neurodevelopmental disorder with microcephaly, short stature, and speech delay
• Neurodevelopmental disorder with poor growth, spastic tetraplegia, and hearing loss
• Neurodevelopmental disorder with seizures, microcephaly, and brain abnormalities
• Neurodevelopmental disorder with short stature, prominent forehead, and feeding difficulties
• Neuronopathy, distal hereditary motor, 10
• Orofaciodigital syndrome 19
• Polycystic kidney disease 7
• Retinitis pigmentosa 95
• Spermatogenic failure 76
• Spermatogenic failure 77

Modified diseases:

• Angioedema, hereditary -> Angioedema, hereditary, 1
• Autism 18 -> Intellectual developmental disorder with autism and macrocephaly
• Autoimmune lymphoproliferative syndrome 5 -> Immune dysregulation with autoimmunity, immunodeficiency, and lymphoproliferation
• Bent bone dysplasia syndrome -> Bent bone dysplasia syndrome 1
• Candidiasis, familial, 2 -> Immunodeficiency 103, susceptibility to fungal infections
• Cardiac valvular defect, developmental -> Cardiac valvular dysplasia 1
• Carey-Fineman-Ziter syndrome -> Carey-Fineman-Ziter syndrome 1
• Cleidocranial dysplasia -> Cleidocranial dysplasia 1
• Combined oxidative phosphorylation deficiency 26 -> Peripheral neuropathy with variable spasticity, exercise intolerance, and developmental dela
• Congenital disorder of glycosylation 1W -> Congenital disorder of glycosylation 1W, autosomal recessive
• Craniofacial dysmorphism, skeletal anomalies and intellectual disability syndrome -> Craniofacial dysmorphism, skeletal anomalies and impaired intellectual development syndrome 1
• Craniofacial dysmorphism, skeletal anomalies and intellectual disability syndrome 2 -> Craniofacial dysmorphism, skeletal anomalies and impaired intellectual development syndrome 2
• Deafness, autosomal recessive, 70 -> Deafness, autosomal recessive, 70, with or without adult-onset neurodegeneration
• Developmental and epileptic encephalopathy 39 -> Developmental and epileptic encephalopathy 39 with leukodystrophy
• Developmental delay with short stature, dysmorphic facial features, and sparse hair -> Developmental delay with short stature, dysmorphic facial features, and sparse hair 1
• Diabetes insipidus, nephrogenic, autosomal -> Diabetes insipidus, nephrogenic, 2, autosomal
• Diabetes insipidus, nephrogenic, X-linked -> Diabetes insipidus, nephrogenic, 1, X-linked
• Diabetes mellitus, insulin-dependent, 10 -> Type 1 diabetes mellitus 10
• Diabetes mellitus, insulin-dependent, 12 -> Type 1 diabetes mellitus 12
• Diabetes mellitus, insulin-dependent, 19 -> Type 1 diabetes mellitus 19
• Diabetes mellitus, insulin-dependent, 2 -> Type 1 diabetes mellitus 2
• Diabetes mellitus, insulin-dependent, 20 -> Type 1 diabetes mellitus 20
• Diabetes mellitus, insulin-dependent, 22 -> Type 1 diabetes mellitus 22
• Diabetes mellitus, insulin-dependent, 5 -> Type 1 diabetes mellitus 5
• Diabetes mellitus, insulin-dependent -> Type 1 diabetes mellitus
• Diabetes mellitus, non-insulin-dependent, 1 -> Type 2 diabetes mellitus 1
• Diabetes mellitus, non-insulin-dependent, 5 -> Type 2 diabetes mellitus 5
• Diabetes mellitus, non-insulin-dependent -> Type 2 diabetes mellitus
• Erythroderma, ichthyosiform, congenital reticular -> Ichthyosis with confetti
• Gonadal dysgenesis, dysmorphic facies, retinal dystrophy, and myopathy -> Myoectodermal gonadal dysgenesis syndrome
• Growth hormone deficiency, isolated, 5 -> Pituitary hormone deficiency, combined or isolated, 7
• Hereditary diffuse gastric cancer -> Diffuse gastric and lobular breast cancer syndrome
• Hypertriglyceridemia, familial -> Hypertriglyceridemia 1
• Intellectual developmental disorder, autosomal dominant 30 -> Intellectual developmental disorder, autosomal dominant 30, with speech delay and behavioral abnormalities
• Intellectual developmental disorder and hypogonadotropic hypogonadism -> BDV syndrome
• Leukoencephalopathy, megalencephalic, with subcortical cysts, 2B -> Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without impaired intellectual development
• Leukodystrophy, globoid cell -> Krabbe disease
• Lysyl hydroxylase 3 deficiency -> Bone fragility with contractures, arterial rupture, and deafness
• Macrothrombocytopenia, autosomal dominant, TUBB1-related -> Macrothrombocytopenia, isolated, 1, autosomal dominant
• Metachromatic leukodystrophy due to saposin-B deficiency -> Metachromatic leukodystrophy due to saposin B deficiency
• Neurodegeneration, infantile-onset, biotin-responsive -> Sodium-dependent multivitamin transporter deficiency
• Neurodevelopmental disorder with spastic quadriplegia, optic atrophy, seizures, and structural brain anomalies -> Halperin-Birk syndrome
• Olmsted syndrome -> Olmsted syndrome 1
• Opitz GBBB syndrome 1 -> Opitz GBBB syndrome
• Pelger-Huet anomaly with mild skeletal anomalies -> Rhizomelic skeletal dysplasia with or without Pelger-Huet anomaly
• Portal hypertension, non-cirrhotic -> Portal hypertension, non-cirrhotic, 1
• Primary bile acid malabsorption -> Bile acid malabsorption, primary, 1
• Psychomotor retardation, epilepsy, and craniofacial dysmorphism -> Neurodevelopmental disorder with hypotonia, craniofacial abnormalities, and seizures
• Severe combined immunodeficiency autosomal recessive T-cell-negative/B-cell-positive/NK-cell-positive -> Immunodeficiency 104
• Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies -> Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 1
• Short stature, rhizomelic, with microcephaly, micrognathia, and developmental delay -> Short stature-micrognathia syndrome
• Stuve-Wiedemann syndrome -> Stuve-Wiedemann syndrome 1
• Thyroid hormone metabolism, abnormal -> Thyroid hormone metabolism, abnormal, 1
• Tumor predisposition syndrome -> Tumor predisposition syndrome 1
• Triphalangeal thumb-polysyndactyly syndrome -> Triphalangeal thumb with polysyndactyly
• Ventricular tachycardia, catecholaminergic polymorphic, 5, with or without muscle weakness -> Cardiac arrhythmia syndrome, with or without skeletal muscle weakness

Deleted diseases

• Prolactin-secreting pituitary adenoma
• Retinitis pigmentosa autosomal recessive

Changes to the controlled vocabulary for PTMs

New term for the feature key 'Lipidation' ('LIPID' in the flat file):

• N6-decanoyllysine

UniParc news

Change of the UniParc files distribution

The UniParc database is distributed on the UniProt FTP site in FASTA and XML format as one gzip-compressed file for each format. The size of these files has grown over the years to now more that 100 and 200 Gigabytes, respectively, which makes them difficult to download. We now therefore split these files into sets of 128 smaller files each. The partitioned files are available in the following subdirectories:

https://ftp.uniprot.org/pub/databases/uniprot/current_release/uniparc/xml/all	all sequences in XML format
https://ftp.uniprot.org/pub/databases/uniprot/current_release/uniparc/fasta/active	all active sequences in FASTA format

For release 2023_01, we are providing each format as one file and partitioned into 128 smaller files. From release 2023_02 onwards, only the partitioned files will be provided.

Headline

Plant adaptation to global warming through epigenetic memory

While we humans are organizing large conferences to find ways to limit global warming, plants elaborate sophisticated epigenetic strategies to adapt to it. Plant exposure to heat activates various genes and repetitive elements, that are normally silenced via transcriptional gene silencing, and releases post-transcriptional gene silencing by inhibiting siRNA biogenesis. Heat responses are usually transient and reset quickly to normal conditions, although there is some somatic stress memory with a duration of several days. However, certain plant responses can also be transmitted to the next unstressed generation.

In 2014, Migicovsky et al. reported that extreme heat (50°C)-stressed Arabidopsis thaliana show accelerated flowering and this phenotype was also observed in the immediate unstressed progeny, where it is maternally transmitted. Recently certain molecular aspects of this phenomenon have been unraveled. By comparing gene expression in heat-stressed A. thaliana and in its unstressed second generation progeny, which both exhibit the same early flowering phenotype, Liu et al. observed that the SGS3 gene was down-regulated in both generations. SGS3 is essential for the biogenesis of trans-acting siRNAs. The resulting decrease in siRNAs leads to the up-regulation of HTT5, a protein required for early flowering. SGS3 down-regulation was mediated by the E3 ubiquitin-protein ligase SGIP1, which is up-regulated following heat stress and targets SGS3 to proteasomal degradation. Liu et al. explored further upstream to find the regulators of this cascade of events and found two genes whose expression was induced by heat. They are the heat shock transcription factor HSFA2 that directly activates the H3K27me3 demethylase REF6. REF6 in turn derepresses the HSFA2 gene, which together establish a heritable feedback loop. REF6 and HSFA2 activate SGIP1 and HTT5 transcription in concert. In conclusion, H3K27me3 demethylation and HSFA2 activation might be key events in the pathway of heat sensing in plants. The actual primary heat sensors are still elusive and the transmission of thermomemory remains a mystery. It should be noted, however, that it is not the first time that epigenetic memory transmission was reported. In C. elegans, exposure to bisphenol A causes the derepression of an epigenomically silenced transgene in the germline for 5 generations. This effect was associated with a reduction of the repressive marks H3K9me3 and H3K27me3.

Accelerating reproductive development has a cost for A. thaliana. HTT5 is not only involved in early flowering, but it also attenuates disease resistance. In this context, evolution has chosen growth over defense.

The updated UniProtKB/Swiss-Prot entries for A. thaliana REF6, HSFA2, as well as their downstream targets SGIP1, SGS3 and HTT5 are available in the knowledgebase.

UniProtKB news

Cross-references to AGR

Cross-references have been added to the Alliance of Genome Resources (AGR).

AGR is available at https://alliancegenome.org/.

The format of the explicit links is:

Resource abbreviation	AGR
Resource identifier	Resource identifier

Example: Q20646

Show all entries having a cross-reference to AGR.

Text format

Example: Q20646

DR   AGR; WB:WBGene00000467; -.

XML format

Example: Q20646

<dbReference type="AGR" id="WB:WBGene00000467"/>

RDF format

Example: Q20646

uniprot:Q20646
  rdfs:seeAlso <http://purl.uniprot.org/agr/WB:WBGene00000467> .
<http://purl.uniprot.org/agr/WB:WBGene00000467>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/AGR> .

Changes to the controlled vocabulary of human diseases

New diseases:

• ACCES syndrome
• Advanced sleep phase syndrome, familial, 4
• Arthrogryposis, distal, 11
• Attention deficit-hyperactivity disorder 8
• Braddock-Carey syndrome 2
• Cardiomyopathy, dilated 2G
• Carey-Fineman-Ziter syndrome 2
• Cholestasis, progressive familial intrahepatic, 12
• Corneal dystrophy, punctiform and polychromatic pre-Descemet
• Craniofacial dysmorphism, skeletal anomalies and intellectual disability syndrome 2
• Dentici-Novelli neurodevelopmental syndrome
• Developmental and epileptic encephalopathy 102
• Developmental and epileptic encephalopathy 103
• Developmental and epileptic encephalopathy 104
• Developmental and epileptic encephalopathy 105 with hypopituitarism
• Developmental delay, hypotonia, and impaired language.
• Developmental delay, impaired speech, and behavioral abnormalities, with or without seizures
• Distal spinal muscular atrophy, autosomal recessive, 6
• Dworschak-Punetha neurodevelopmental syndrome
• Dystonia 35, childhood-onset
• Glycosylphosphatidylinositol biosynthesis defect 25
• Hemolytic anemia due to elevated adenosine deaminase
• Hepatorenocardiac degenerative fibrosis
• Holoprosencephaly 14
• Hypothyroidism, congenital, non-goitrous, 4
• Immunodeficiency 100 with pulmonary alveolar proteinosis and hypogammaglobulinemia
• Immunodeficiency 101, varicella zoster virus-specific
• Immunodeficiency 102
• Immunodeficiency 105
• Immunodeficiency 106, susceptibility to viral infections
• Immunodeficiency 107, susceptibility to invasive Staphylococcus aureus infection
• Intellectual developmental disorder, autosomal dominant 66
• Intellectual developmental disorder, autosomal dominant 67
• Intellectual developmental disorder, autosomal dominant 68
• Intellectual developmental disorder, autosomal dominant 69
• Intellectual developmental disorder, autosomal recessive 76
• Intellectual developmental disorder, autosomal recessive 77
• Intellectual developmental disorder with language impairment and early-onset DOPA-responsive dystonia-parkinsonism
• Intellectual developmental disorder with muscle tone abnormalities and distal skeletal defects
• Keratoderma-ichthyosis-deafness syndrome, autosomal recessive
• Knobloch syndrome 2
• Liver disease, severe congenital
• Lymphatic malformation 12
• Macular dystrophy, retinal, 4
• Meckel syndrome 14
• Melanoma, uveal, 1
• Melanoma, uveal, 2
• Myopathy, congenital, non-progressive
• Neurocardiofaciodigital syndrome
• Neurodevelopmental disorder with dystonia and seizures
• Neurodevelopmental disorder with epilepsy and brain atrophy
• Neurodevelopmental disorder with intention tremor, pyramidal signs, dyspraxia, and ocular anomalies
• Neurodevelopmental disorder with language delay and seizures
• Neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizures
• Neurodevelopmental disorder with poor growth and skeletal anomalies
• Neurodevelopmental disorder with severe motor impairment, absent language, cerebral hypomyelination, and brain atrophy
• Neurodevelopmental disorder with spasticity, seizures, and brain abnormalities
• Neurodevelopmental disorder with speech delay and variable ocular anomalies
• Osteoporosis, childhood- or juvenile-onset, with developmental delay
• Parenti-Mignot neurodevelopmental syndrome
• Peripheral motor neuropathy, childhood-onset, biotin-responsive
• Pontocerebellar hypoplasia 17
• Premature ovarian failure 20
• Primordial dwarfism-immunodeficiency-lipodystrophy syndrome
• Pulmonary hypertension, primary, 5
• Renal hypodysplasia/aplasia 4
• Retinitis pigmentosa 94, variable age at onset, autosomal recessive
• Spastic paraplegia 87, autosomal recessive
• Spinocerebellar ataxia 25
• Spermatogenic failure 2
• Spermatogenic failure 75
• Stickler syndrome 6
• Tessadori-van Haaften neurodevelopmental syndrome 3
• Tessadori-van Haaften neurodevelopmental syndrome 4
• Tumor predisposition syndrome 2
• Waardenburg syndrome 2F

Modified diseases:

• Hyper-IgE recurrent infection syndrome 4, autosomal recessive -> Hyper-IgE recurrent infection syndrome 4B, autosomal recessive
• Intellectual developmental disorder, autosomal recessive 53 -> Neurodevelopmental disorder with or without hypotonia, seizures, and cerebellar atrophy
• Retinal macular dystrophy 2 -> Macular dystrophy, retinal, 2

Headline

The (phenolic) Rings of Power

When walking in the countryside, you may have noticed very small insects with very delicate white wings, looking a little like tiny butterflies, flitting around when a leaf or a stem is disturbed. In spite of their harmless appearance, whiteflies, including Bemisia tabaci, are a pest that not only causes damage by feeding on plant sap, but is also a vector for a multitude of plant viruses and causes major crop loss around the world. Whiteflies are able to attack over 600 plant species. Luckily many plants have developed efficient anti-herbivore chemicals for their defense. These include phenolic glycosides, which strongly affect growth, development, and behavior of insect herbivores. Phenolic glycosides are also toxic to the plants that produce them, but plants detoxify them by attaching a malonyl group to phenolic glucosides, a reaction catalyzed by malonyltransferases. Malonylated glycosides can then be safely stored in plant vacuoles. Incidentally this process is also used by plants for xenobiotic detoxification, and can lead to herbicide resistance, for instance.

In tomato leaves, some 290 different phenolic glycosides have been identified, several of which have been shown to be toxic to B. tabaci only when ingested at higher doses than those found in plant phloem. Where does this insect resistance to physiological levels of phenolic glycosides come from? Thorough examination of B. tabaci genes led to the discovery of BtPMaT1, a gene encoding an insect glucoside malonyltrasferase. BtPMaT1 is widely expressed in B. tabaci at all stages of life, with highest levels in the adult gut, a perfect location for food detoxification. Feeding B. tabaci on transgenic tomatoes, expressing BtPMaT1 gene fragments that efficiently silence BtPMaT1, leads to increased whitefly mortality and decreased malonylated flavonoid glycosides in honeydew, convincingly demonstrating that BtPMaT1 catalyzes malonylation of phenolic glycosides in vivo.

B. tabaci BtPMaT1 gene has no homologue in other arthropods, not even in the related greenhouse whitefly, Trialeurodes vaporariorum, but it carries significant similarity to plant enzymes. Phylogenetic analysis shows BtPMaT1 clusters within a group of plant BAHD acyltransferases. All evidence points to one conclusion: BtPMaT1 has been horizontally acquired from plants. The horizontal transfer must have taken place after the divergence from Trialeurodes (some 86 million years ago). Horizontal transfer is a well-known process in prokaryotes, but we are just beginning to appreciate its importance in the adaptive evolution of eukaryotes.

Happily, you don't have to wait 80 million years to find the newly created UniProtKB/Swiss-Prot BtPMaT1 entry which is now available in our knowledgebase.

UniProtKB news

Google protein name predictions

UniProt has collaborated with the groups of Max Bileschi and Lucy Colwell at Google Research to predict names for UniProtKB/TrEMBL proteins. The UniProt 2021_02 release data were used to train a model called ProtNLM based on the T5X framework. The model uses a shared vocabulary that encodes both protein sequences and their text descriptions (T5 methodology, Raffel et al. 2020). Free-text UniProt protein name(s) are produced as output. Expert biocurators manually evaluated a subset of model-predicted protein names chosen at random and informed model-building with stratified confidence scores. An automated verification tool also checked whether a predicted name occurs as a substring of the full UniProt entry for any protein belonging to the same UniRef50 2022_01 cluster.

Starting from release 2022_04, these name predictions will be used as the recommended name for all TrEMBL entries whose name would otherwise be "Uncharacterized protein" (49,292,040 entries in this release). The source of these protein names is indicated in their evidence tags and can be used to retrieve the corresponding entries with this query.

Protein embeddings

Protein embeddings are a way to encode functional and structural properties of a protein, mostly from its sequence only, in a machine-friendly format (vector representation). Generating such embeddings is computationally expensive, but once computed they can be leveraged for different tasks, such as sequence similarity search, sequence clustering, and sequence classification.

Starting from release 2022_04, UniProt is providing raw embeddings (per-protein and per-residue using the ProtT5 model) for UniProtKB/Swiss-Prot and the reference proteomes of the model organisms listed below:

• Homo sapiens
• Mus musculus
• Rattus norvegicus
• Arabidopsis thaliana
• Caenorhabditis elegans
• Escherichia coli
• SARS-CoV-2

You can download the embeddings from our Downloads page.

Changes to the controlled vocabulary of human diseases

New diseases:

• 3-methylglutaconic aciduria 7A
• Agammaglobulinemia 8B, autosomal recessive
• Aortic aneurysm, familial thoracic 12
• Auditory neuropathy, autosomal dominant 3
• Autoinflammatory disease, systemic, X-linked
• Autoinflammatory syndrome, familial, X-linked, Behcet-like 2
• Autoinflammatory-pancytopenia syndrome
• Chilton-Okur-Chung neurodevelopmental syndrome
• Cholestasis, progressive familial intrahepatic, 9
• Cholestasis, progressive familial intrahepatic, 10
• Cholestasis, progressive familial intrahepatic, 11
• Deafness, autosomal dominant, 21
• Deafness, autosomal dominant, 83
• Deafness, autosomal dominant, 84
• Hypoalphalipoproteinemia, primary, 2, intermediate
• Immunodeficiency 97 with autoinflammation
• Immunodeficiency 98 with autoinflammation, X-linked
• Immunodeficiency 99 with hypogammaglobulinemia and autoimmune cytopenias
• Intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly
• Intellectual developmental disorder, X-linked, syndromic, Pilorge type
• Intellectual developmental disorder with or without peripheral neuropathy
• Leukodystrophy, childhood-onset, remitting
• Leukodystrophy, hypomyelinating, 24
• Macrothrombocytopenia, isolated, 2, autosomal dominant
• Myopathy, distal, 7, adult-onset, X-linked
• Neurodegeneration, childhood-onset, with progressive microcephaly
• Neurodevelopmental disorder with epilepsy and hemochromatosis
• Neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities
• Neurodevelopmental disorder with neuromuscular and skeletal abnormalities
• Neutropenia, severe congenital 9, autosomal dominant
• Ovarian dysgenesis 10
• Phosphoribosylaminoimidazole carboxylase deficiency
• Retinitis pigmentosa 93
• Spermatogenic failure, X-linked, 4
• Spermatogenic failure 69
• Spermatogenic failure 70
• Spermatogenic failure 71
• Spermatogenic failure 72
• Spermatogenic failure 73
• Spermatogenic failure 74
• Spinocerebellar ataxia, autosomal recessive, 32
• Spinocerebellar ataxia 49
• Systemic lupus erythematosus 17
• Thyroid hormone metabolism, abnormal, 2

Modified diseases:

• 3-methylglutaconic aciduria 7 -> 3-methylglutaconic aciduria 7B
• Agammaglobulinemia 8, autosomal dominant -> Agammaglobulinemia 8A, autosomal dominant
• Arthrogryposis, intellectual disability, and seizures -> Arthrogryposis, impaired intellectual development, and seizures
• Auditory neuropathy, autosomal dominant, 1 -> Auditory neuropathy, autosomal dominant 1
• Autoinflammatory syndrome, familial, Behcet-like -> Autoinflammatory syndrome, familial, Behcet-like 1
• Diarrhea 2, with microvillus atrophy -> Diarrhea 2, with microvillus atrophy, with or without cholestasis
• Epidermolysis bullosa, junctional, Herlitz type -> Epidermolysis bullosa, junctional 1B, severe
• Epidermolysis bullosa, non-specific, autosomal recessive -> Epidermolysis bullosa simplex 4, localized or generalized intermediate, autosomal recessive
• Epidermolysis bullosa letalis, with pyloric atresia -> Epidermolysis bullosa, junctional 5B, with pyloric atresia
• Epidermolysis bullosa simplex, autosomal recessive 1 -> Epidermolysis bullosa simplex 1D, generalized, intermediate or severe, autosomal recessive
• Epidermolysis bullosa simplex, autosomal recessive 2 -> Epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency
• Epidermolysis bullosa simplex, Dowling-Meara type -> Epidermolysis bullosa simplex 1A, generalized severe
• Epidermolysis bullosa simplex, generalized, with scarring and hair loss -> Epidermolysis bullosa simplex 6, generalized, with scarring and hair loss
• Epidermolysis bullosa simplex, Koebner type -> Epidermolysis bullosa simplex 1B, generalized intermediate
• Epidermolysis bullosa simplex, Ogna type -> Epidermolysis bullosa simplex 5A, Ogna type
• Epidermolysis bullosa simplex, Weber-Cockayne type -> Epidermolysis bullosa simplex 1C, localized
• Epidermolysis bullosa simplex, with muscular dystrophy -> Epidermolysis bullosa simplex 5B, with muscular dystrophy
• Epidermolysis bullosa simplex with nail dystrophy -> Epidermolysis bullosa simplex 5D, generalized intermediate, autosomal recessive
• Epidermolysis bullosa simplex with pyloric atresia -> ""Epidermolysis bullosa simplex 5C, with pyloric atresia:/diseases/DI-01532
• Generalized atrophic benign epidermolysis bullosa -> Epidermolysis bullosa, junctional 1A, intermediate
• Intellectual disability with language impairment and autistic features -> Intellectual developmental disorder with language impairment and with or without autistic features
• Interstitial lung disease, nephrotic syndrome, and epidermolysis bullosa, congenital -> Epidermolysis bullosa, junctional 7, with interstitial lung disease and nephrotic syndrome
• Laryngoonychocutaneous syndrome -> Epidermolysis bullosa, junctional 2C, laryngoonychocutaneous
• Lethal tight skin contracture syndrome -> Restrictive dermopathy 1
• Nephropathy with pretibial epidermolysis bullosa and deafness -> Epidermolysis bullosa simplex 7, with nephropathy and deafness
• Spastic paraplegia 56, autosomal recessive -> Spastic paraplegia 56, autosomal recessive, with or without pseudoxanthoma elasticum

Changes to the controlled vocabulary for PTMs

New term for the feature key 'Modified residue' ('MOD_RES' in the flat file):

• ADP-ribosylthreonine

Headline

Not just for proteins: new targets for ADP-ribosylation

ADP-ribosylation is a modification which transfers ADP-ribose from NAD(+) onto substrates. It is involved in a number of crucial functions, ranging from stress responses elicited, for example, by DNA damage and viral infection, to intra-and extracellular signaling, chromatin and transcriptional regulation, protein biosynthesis, and cell death. ADP-ribosylation of proteins has been extensively studied, and numerous enzymes catalyzing this reaction have been identified in eukaryotes. For instance the poly [ADP-ribose] polymerase PARP1, which is activated in response to DNA damage, or the poly [ADP-ribose] polymerase tankyrases, such as TNKS, which are involved in processes such as the Wnt signalling pathway, telomere length regulation and vesicle trafficking. A number of bacterial toxins are protein ADP-ribosyltransferases, such as diphtheria toxin or Pseudomonas aeruginosa exotoxin A, which ADP-ribosylate eukaryotic elongation factor 2, arresting protein synthesis or SpvB from Salmonella dublin, which ADP-ribosylates host actin, preventing its polymerization and causing actin depolymerization, cytoskeleton destruction and cytotoxicity.

But ADP-ribosylation is not just for proteins. It has been known since at least 1999 that DNA can be modified. For over 20 years, this process was investigated by the group of Keiji Wakabayashi, who was working on pierisin, a cytotoxin found in late-stage larvae and pupae of the cabbage white butterfly Pieris rapae. Pierisin ADP-ribosylates double-stranded DNA (dsDNA) on the N2 group of deoxyguanosine. ADP-ribosylation of DNA is detected as DNA damage by the cell machinery and leads to apoptosis. This process is thought to protect the butterfly embryo against parasitic wasps. Later on it was shown that mammalian PARP1, the well-characterized protein ADP-ribosyltransferase mentioned above, can also modify DNA strand break termini.

Recently DarT, another DNA-targeted ADP-ribosyltransferase, has been discovered in Mycobacterium tuberculosis. DarT belongs to a novel toxin-antitoxin (TA) system. It recognizes and modifies a specific thymidine in single-stranded DNA (ssDNA) at the origin of chromosomal replication, which is perceived as severe DNA damage, leading to growth arrest and eventually cell death. This effect is reversed by the DarG antitoxin, which specifically removes ADP-ribosylated DNA adducts and functions as a noncanonical DNA repair factor. What is the benefit of the DarT-DarG TA system for M. tuberculosis? It is known that carefully controlled, slow and nonreplicating growth states are key for M.tuberculosis, resulting in persistent, potentially life-long infection and antibiotic tolerance. M.tuberculosis has over 80 TA modules, which are thought to contribute to persistence. DarTG is the most recent addition to this arsenal.

Finally, ADP-ribosylation can also occur on single nucleosides/nucleotides. The soil bacterium Streptomyces coelicolor secretes a guanine-specific ADP-ribosyltransferase, called ScARP. ScARP ADP-ribosylates guanosine and deoxyguanosine, as well as their phosphorylated derivatives GMP, dGMP, GDP, GTP, dGTP, and cyclic GMP. Extracellular ScARP probably finds its guanine substrates from surrounding cells. Many bacteria use guanosine derivatives in response to environmental changes, to regulate their motility, for instance. ScARP may dysregulate these signals by direct ADP-ribosylation of guanosine derivatives, or by synthesizing ADP-ribosylguanosine as a mimicking or competitively inhibiting molecule. The presence of ADP-ribosylguanosine in the nucleotide pool might also induce genomic instability and gene mutation in competitor bacteria living near S.coelicolor. Chemical/biological warfare at a microscopic level!

The non-protein targeted ADP-ribosyltransferases mentioned above have all been recently updated and are available in this release of UniProtKB. While annotating these enzymes, we created many new Rhea reactions, which also required the integration of new molecules at ChEBI. The interconnectedness of databases grows quickly these days!

UniProtKB news

Annotation of biologically relevant ligands in UniProtKB using ChEBI

UniProtKB provides descriptions of the nature and binding sites of biologically relevant ligands that are essential for protein function, such as activators, inhibitors, cofactors, and substrates. We have replaced the existing textual descriptions of these ligands with their equivalents from the ChEBI (Chemical Entities of Biological Interest) ontology to provide high quality computationally tractable annotation of biologically relevant ligands and their binding sites in proteins in UniProtKB. This enhanced dataset provides improved support for efforts to study and predict functionally relevant interactions between proteins and small molecule ligands.

The impact of this change on the UniProtKB data model is described in the following subsections.

Deprecation of 'Calcium binding', 'Metal' and 'Nucleotide binding' annotation types

Historically, UniProtKB has described a few classes of ligand binding sites with dedicated annotation types to make it easier to query them. This has been the case for 'Calcium binding', 'Metal binding' and 'Nucleotide binding'. With the switch to the ChEBI ontology for ligand classification this is no longer necessary, and we have deprecated these annotation types and converted the existing data to 'Binding site' annotations.

Structuring of 'Binding site' annotations

We have structured 'Binding site' annotations in a way that allows us to standardize the description of a ligand, and optionally the bound part of the ligand, with the ChEBI ontology. The vast majority of ligands that are curated in UniProKB are small molecules that can be represented by a ChEBI entity. A minority of curated ligands are macromolecules. These are not within the scope of ChEBI, but ChEBI contains a limited set of high-level terms (such as DNA or RNA) that we use to curate such ligands. For macromolecules and chelating structures, we sometimes (if known and of interest) also describe the bound part of the ligand with a separate ChEBI entity.

In the subsections that describe the new representation of 'Binding site' annotations in different UniProtKB formats we use the following placeholders for annotation values:

Ligand:

Placeholders for values that describe the molecule (small or macro), ion or chelating structure that is bound by the protein:

• LigandName: The UniProt ChEBI name of the ligand, or the word "substrate". Mandatory.
• LigandId: The ChEBI identifier of the ligand. Mandatory, except when the LigandName is "substrate".
• LigandLabel: A label used to distinguish individual instances of a ligand when a protein binds multiple ligands of the same chemical nature. Optional.
• LigandNote: A free text note that provides further details about the ligand. Optional.

Ligand part:

Placeholders for values that describe the specific part of the ligand that is bound by the protein (e.g. the iron atom in a heme, a specific type of amino-acid residue in a protein, the 3'-CCA end of a tRNA molecule):

• LigandPartName: The UniProt ChEBI name of the ligand part. Optional.
• LigandPartId: The ChEBI identifier of the ligand part. Optional.
• LigandPartLabel: A label used to distinguish individual instances of a ligand part when a protein binds multiple parts of the same chemical nature that are part of the same ligand. Optional.
• LigandPartNote: A free text note that provides further details about the ligand part. Optional.

Additional information:

Placeholders for values that provide additional information:

• Note: Free text note about the binding residue(s). Optional.
• Evidences: List of evidences that support the annotation. Optional.

Note also that we continue to use 'Binding site' annotations primarily to describe individual amino acid residues that bind a ligand, but in order to standardize the existing ligand binding descriptions of the annotation types that have been deprecated, as well those of some 'Region' annotations, 'Binding site' annotations may now also describe a range of amino acids when the exact ligand binding residues are unknown or where adjacent ligand binding residues had been grouped in the past.

Text format

We have made the following changes to the UniProtKB text format to standardize the description of a ligand, and optionally the bound part of the ligand, with the ChEBI ontology.

• We have deprecated the feature types CA_BIND, METAL and NP_BIND.
• We have introduced eight new qualifiers for the BINDING feature type to describe a ligand (/ligand, /ligand_id, /ligand_label, /ligand_note) and a ligand part (/ligand_part, /ligand_part_id, /ligand_part_label, /ligand_part_note).
• The representation of the annotation Note and the Evidences remains unchanged.

FT   BINDING         x[..y]
FT                   /ligand="LigandName"
FT                   /ligand_id="ChEBI:LigandId"
FT                   /ligand_label="LigandLabel"
FT                   /ligand_note="LigandNote"
FT                   /ligand_part="LigandPartName"
FT                   /ligand_part_id="ChEBI:LigandPartId"
FT                   /ligand_part_label="LigandPartLabel"
FT                   /ligand_part_note="LigandPartNote"
FT                   /note="Note"
FT                   /evidence="Evidences"

Example: Q9H5X1

Previous format:

FT   METAL           89
FT                   /note="Zinc 1; shared with dimeric partner"
FT   METAL           89
FT                   /note="Zinc 2; shared with dimeric partner"
FT   METAL           123
FT                   /note="Zinc 1; shared with dimeric partner"
FT   METAL           123
FT                   /note="Zinc 2; shared with dimeric partner"

New format:

FT   BINDING         89
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="1"
FT                   /ligand_note="ligand shared between dimeric partners"
FT   BINDING         89
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="2"
FT                   /ligand_note="ligand shared between dimeric partners"
FT   BINDING         123
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="1"
FT                   /ligand_note="ligand shared between dimeric partners"
FT   BINDING         123
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="2"
FT                   /ligand_note="ligand shared between dimeric partners"

Example: P39186

Previous format:

FT   METAL           79
FT                   /note="Iron (heme C 1 axial ligand); via tele nitrogen"
FT   METAL           97
FT                   /note="Iron (heme C 1 axial ligand); via tele nitrogen"
FT   METAL           114
FT                   /note="Iron (heme C 2 axial ligand); via tele nitrogen"
FT   METAL           137
FT                   /note="Iron (heme C 2 axial ligand); via tele nitrogen"
FT   BINDING         93
FT                   /note="Heme C 1; covalent"
FT                   /evidence="ECO:0000269|PubMed:21419779"
FT   BINDING         96
FT                   /note="Heme C 1; covalent"
FT                   /evidence="ECO:0000269|PubMed:21419779"
FT   BINDING         133
FT                   /note="Heme C 2; covalent"
FT                   /evidence="ECO:0000269|PubMed:21419779"
FT   BINDING         136
FT                   /note="Heme C 2; covalent"
FT                   /evidence="ECO:0000269|PubMed:21419779"

New format:

FT   BINDING         79
FT                   /ligand="heme c"
FT                   /ligand_id="ChEBI:CHEBI:61717"
FT                   /ligand_label="1"
FT                   /ligand_part="Fe"
FT                   /ligand_part_id="ChEBI:CHEBI:18248"
FT                   /note="axial binding residue"
FT                   /evidence="ECO:0000269|PubMed:21419779,
FT                   ECO:0007744|PDB:3ML1"
FT   BINDING         93
FT                   /ligand="heme c"
FT                   /ligand_id="ChEBI:CHEBI:61717"
FT                   /ligand_label="1"
FT                   /note="covalent"
FT                   /evidence="ECO:0000269|PubMed:21419779,
FT                   ECO:0007744|PDB:3ML1"
FT   BINDING         96
FT                   /ligand="heme c"
FT                   /ligand_id="ChEBI:CHEBI:61717"
FT                   /ligand_label="1"
FT                   /note="covalent"
FT                   /evidence="ECO:0000269|PubMed:21419779,
FT                   ECO:0007744|PDB:3ML1"
FT   BINDING         97
FT                   /ligand="heme c"
FT                   /ligand_id="ChEBI:CHEBI:61717"
FT                   /ligand_label="1"
FT                   /ligand_part="Fe"
FT                   /ligand_part_id="ChEBI:CHEBI:18248"
FT                   /note="axial binding residue"
FT                   /evidence="ECO:0000269|PubMed:21419779,
FT                   ECO:0007744|PDB:3ML1"
FT   BINDING         114
FT                   /ligand="heme c"
FT                   /ligand_id="ChEBI:CHEBI:61717"
FT                   /ligand_label="2"
FT                   /ligand_part="Fe"
FT                   /ligand_part_id="ChEBI:CHEBI:18248"
FT                   /note="axial binding residue"
FT                   /evidence="ECO:0000269|PubMed:21419779,
FT                   ECO:0007744|PDB:3ML1"
FT   BINDING         133
FT                   /ligand="heme c"
FT                   /ligand_id="ChEBI:CHEBI:61717"
FT                   /ligand_label="2"
FT                   /note="covalent"
FT                   /evidence="ECO:0000269|PubMed:21419779,
FT                   ECO:0007744|PDB:3ML1"
FT   BINDING         136
FT                   /ligand="heme c"
FT                   /ligand_id="ChEBI:CHEBI:61717"
FT                   /ligand_label="2"
FT                   /note="covalent"
FT                   /evidence="ECO:0000269|PubMed:21419779,
FT                   ECO:0007744|PDB:3ML1"
FT   BINDING         137
FT                   /ligand="heme c"
FT                   /ligand_id="ChEBI:CHEBI:61717"
FT                   /ligand_label="2"
FT                   /ligand_part="Fe"
FT                   /ligand_part_id="ChEBI:CHEBI:18248"
FT                   /note="axial binding residue"
FT                   /evidence="ECO:0000269|PubMed:21419779,
FT                   ECO:0007744|PDB:3ML1"

Example: Q9H6S0

Previous format:

FT   REGION          1294..1296
FT                   /note="N6-methyladenosine residue binding"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Y5A9"
...
FT   BINDING         1310
FT                   /note="N6-methyladenosine residue"
FT                   /evidence="ECO:0000250|UniProtKB:Q96MU7"
FT   BINDING         1360
FT                   /note="N6-methyladenosine residue"
FT                   /evidence="ECO:0000250|UniProtKB:Q96MU7"

New format:

FT   BINDING         1294..1296
FT                   /ligand="RNA"
FT                   /ligand_id="ChEBI:CHEBI:33697"
FT                   /ligand_part="N(6)-methyladenosine 5'-phosphate residue"
FT                   /ligand_part_id="ChEBI:CHEBI:74449"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Y5A9"
FT   BINDING         1310
FT                   /ligand="RNA"
FT                   /ligand_id="ChEBI:CHEBI:33697"
FT                   /ligand_part="N(6)-methyladenosine 5'-phosphate residue"
FT                   /ligand_part_id="ChEBI:CHEBI:74449"
FT                   /evidence="ECO:0000250|UniProtKB:Q96MU7"
FT   BINDING         1360
FT                   /ligand="RNA"
FT                   /ligand_id="ChEBI:CHEBI:33697"
FT                   /ligand_part="N(6)-methyladenosine 5'-phosphate residue"
FT                   /ligand_part_id="ChEBI:CHEBI:74449"
FT                   /evidence="ECO:0000250|UniProtKB:Q96MU7"

XML format

We have made the following changes to the UniProtKB XSD to standardize the description of a ligand, and optionally the bound part of the ligand, with the ChEBI ontology.

• We have deprecated the feature types calcium-binding region, metal ion-binding site and nucleotide phosphate-binding region.
• We have introduced two new elements, ligand and ligandPart, and corresponding types, ligandType and ligandPartType. The two types have the same structure that consists of the following four elements:
  • name for the value LigandName / LigandPartName
  • dbReference for a cross-reference to a ChEBI record (LigandId / LigandPartId)
  • label for the value LigandLabel / LigandPartLabel
  • note for the value LigandNote / LigandPartNote
• The representation of the annotation Note and the Evidences remains unchanged.

<feature type="binding site" description="Note" evidence="Evidences">
      <location>
        ...
      </location>
      <ligand>
        <name>LigandName</name>
        <dbReference type="ChEBI" id="LigandId"/>
        <label>LigandLabel</label>
        <note>LigandNote</note>
      </ligand>
      <ligandPart>
        <name>LigandPartName</name>
        <dbReference type="ChEBI" id="LigandPartId"/>
        <label>LigandPartLabel</label>
        <note>LigandPartNote</note>
      </ligandPart>
    </feature>

The XSD changes are highlighted in red color below:

<!-- Feature definition begins -->
    <xs:complexType name="featureType">
    ...
        <xs:sequence>
        ...
            <xs:element name="location" type="locationType">
                <xs:annotation>
                    <xs:documentation>Describes the sequence coordinates of the annotation.</xs:documentation>
                </xs:annotation>
            </xs:element>
            <xs:element name="ligand" type="ligandType" minOccurs="0">
                <xs:annotation>
                    <xs:documentation>Describes the chemical entity that is bound in annotations that describe binding sites.</xs:documentation>
                </xs:annotation>
            </xs:element>
            <xs:element name="ligandPart" type="ligandPartType" minOccurs="0">
                <xs:annotation>
                    <xs:documentation>Describes the specific part of a molecule that is bound in annotations that describe binding sites.</xs:documentation>
                </xs:annotation>
            </xs:element>
        </xs:sequence>
        <xs:attribute name="type" use="required">
        ...
            <xs:simpleType>
                <xs:restriction base="xs:string">
                    <xs:enumeration value="active site"/>
                    <xs:enumeration value="binding site"/>
                    <!-- <xs:enumeration value="calcium-binding region"/> -->
                    ...
                    <!-- <xs:enumeration value="metal ion-binding site"/> -->
                    ...
                    <!-- <xs:enumeration value="nucleotide phosphate-binding region"/> -->
                    ...
                </xs:restriction>
            </xs:simpleType>
        </xs:attribute>
    ...
    </xs:complexType>
    ...
    <xs:complexType name="ligandType">
        <xs:annotation>
            <xs:documentation>Describes a ligand.</xs:documentation>
        </xs:annotation>
        <xs:sequence>
            <xs:element name="name" type="xs:string"/>
            <xs:element name="dbReference" type="dbReferenceType" minOccurs="0"/>
            <xs:element name="label" type="xs:string" minOccurs="0"/>
            <xs:element name="note" type="xs:string" minOccurs="0"/>
        </xs:sequence>
    </xs:complexType>

    <xs:complexType name="ligandPartType">
        <xs:annotation>
            <xs:documentation>Describes a ligand part.</xs:documentation>
        </xs:annotation>
        <xs:sequence>
            <xs:element name="name" type="xs:string"/>
            <xs:element name="dbReference" type="dbReferenceType" minOccurs="0"/>
            <xs:element name="label" type="xs:string" minOccurs="0"/>
            <xs:element name="note" type="xs:string" minOccurs="0"/>
        </xs:sequence>
    </xs:complexType>

Example: Q9H5X1

Previous format:

<feature type="metal ion-binding site" description="Zinc 1; shared with dimeric partner">
      <location>
        <position position="89"/>
      </location>
    </feature>
    <feature type="metal ion-binding site" description="Zinc 2; shared with dimeric partner">
      <location>
        <position position="89"/>
      </location>
    </feature>
    <feature type="metal ion-binding site" description="Zinc 1; shared with dimeric partner">
      <location>
        <position position="123"/>
      </location>
    </feature>
    <feature type="metal ion-binding site" description="Zinc 2; shared with dimeric partner">
      <location>
        <position position="123"/>
      </location>
    </feature>

New format:

<feature type="binding site">
      <location>
        <position position="89"/>
      </location>
      <ligand>
        <name>Zn(2+)</name>
        <dbReference type="ChEBI" id="CHEBI:29105"/>
        <label>1</label>
        <note>ligand shared between dimeric partners</note>
      </ligand>
    </feature>
    <feature type="binding site">
      <location>
        <position position="89"/>
      </location>
      <ligand>
        <name>Zn(2+)</name>
        <dbReference type="ChEBI" id="CHEBI:29105"/>
        <label>2</label>
        <note>ligand shared between dimeric partners</note>
      </ligand>
    </feature>
    <feature type="binding site">
      <location>
        <position position="123"/>
      </location>
      <ligand>
        <name>Zn(2+)</name>
        <dbReference type="ChEBI" id="CHEBI:29105"/>
        <label>1</label>
        <note>ligand shared between dimeric partners</note>
      </ligand>
    </feature>
    <feature type="binding site">
      <location>
        <position position="123"/>
      </location>
      <ligand>
        <name>Zn(2+)</name>
        <dbReference type="ChEBI" id="CHEBI:29105"/>
        <label>2</label>
        <note>ligand shared between dimeric partners</note>
      </ligand>
    </feature>

Example: P39186

Previous format:

<feature type="metal ion-binding site" description="Iron (heme C 1 axial ligand); via tele nitrogen">
      <location>
        <position position="79"/>
      </location>
    </feature>
    <feature type="metal ion-binding site" description="Iron (heme C 1 axial ligand); via tele nitrogen">
      <location>
        <position position="97"/>
      </location>
    </feature>
    <feature type="metal ion-binding site" description="Iron (heme C 2 axial ligand); via tele nitrogen">
      <location>
        <position position="114"/>
      </location>
    </feature>
    <feature type="metal ion-binding site" description="Iron (heme C 2 axial ligand); via tele nitrogen">
      <location>
        <position position="137"/>
      </location>
    </feature>
    <feature type="binding site" description="Heme C 1; covalent" evidence="2">
      <location>
        <position position="93"/>
      </location>
    </feature>
    <feature type="binding site" description="Heme C 1; covalent" evidence="2">
      <location>
        <position position="96"/>
      </location>
    </feature>
    <feature type="binding site" description="Heme C 2; covalent" evidence="2">
      <location>
        <position position="133"/>
      </location>
    </feature>
    <feature type="binding site" description="Heme C 2; covalent" evidence="2">
      <location>
        <position position="136"/>
      </location>
    </feature>

New format:

<feature type="binding site" description="axial binding residue" evidence="2 5">
      <location>
        <position position="79"/>
      </location>
      <ligand>
        <name>heme c</name>
        <dbReference type="ChEBI" id="CHEBI:61717"/>
        <label>1</label>
      </ligand>
      <ligandPart>
        <name>Fe</name>
        <dbReference type="ChEBI" id="CHEBI:18248"/>
      </ligandPart>
    </feature>
    <feature type="binding site" description="covalent" evidence="2 5">
      <location>
        <position position="93"/>
      </location>
      <ligand>
        <name>heme c</name>
        <dbReference type="ChEBI" id="CHEBI:61717"/>
        <label>1</label>
      </ligand>
    </feature>
    <feature type="binding site" description="covalent" evidence="2 5">
      <location>
        <position position="96"/>
      </location>
      <ligand>
        <name>heme c</name>
        <dbReference type="ChEBI" id="CHEBI:61717"/>
        <label>1</label>
      </ligand>
    </feature>
    <feature type="binding site" description="axial binding residue" evidence="2 5">
      <location>
        <position position="97"/>
      </location>
      <ligand>
        <name>heme c</name>
        <dbReference type="ChEBI" id="CHEBI:61717"/>
        <label>1</label>
      </ligand>
      <ligandPart>
        <name>Fe</name>
        <dbReference type="ChEBI" id="CHEBI:18248"/>
      </ligandPart>
    </feature>
    <feature type="binding site" description="axial binding residue" evidence="2 5">
      <location>
        <position position="114"/>
      </location>
      <ligand>
        <name>heme c</name>
        <dbReference type="ChEBI" id="CHEBI:61717"/>
        <label>2</label>
      </ligand>
      <ligandPart>
        <name>Fe</name>
        <dbReference type="ChEBI" id="CHEBI:18248"/>
      </ligandPart>
    </feature>
    <feature type="binding site" description="covalent" evidence="2 5">
      <location>
        <position position="133"/>
      </location>
      <ligand>
        <name>heme c</name>
        <dbReference type="ChEBI" id="CHEBI:61717"/>
        <label>2</label>
      </ligand>
    </feature>
    <feature type="binding site" description="covalent" evidence="2 5">
      <location>
        <position position="136"/>
      </location>
      <ligand>
        <name>heme c</name>
        <dbReference type="ChEBI" id="CHEBI:61717"/>
        <label>2</label>
      </ligand>
    </feature>
    <feature type="binding site" description="axial binding residue" evidence="2 5">
      <location>
        <position position="137"/>
      </location>
      <ligand>
        <name>heme c</name>
        <dbReference type="ChEBI" id="CHEBI:61717"/>
        <label>2</label>
      </ligand>
      <ligandPart>
        <name>Fe</name>
        <dbReference type="ChEBI" id="CHEBI:18248"/>
      </ligandPart>
    </feature>

Example: Q9H6S0

Previous format:

<feature type="region of interest" description="N6-methyladenosine residue binding" evidence="3">
      <location>
        <begin position="1294"/>
        <end position="1296"/>
      </location>
    </feature>
    ...
    <feature type="binding site" description="N6-methyladenosine residue" evidence="2">
      <location>
        <position position="1310"/>
      </location>
    </feature>
    <feature type="binding site" description="N6-methyladenosine residue" evidence="2">
      <location>
        <position position="1360"/>
      </location>
    </feature>

New format:

<feature type="binding site" evidence="3">
      <location>
        <begin position="1294"/>
        <end position="1296"/>
      </location>
      <ligand>
        <name>RNA</name>
        <dbReference type="ChEBI" id="CHEBI:33697"/>
      </ligand>
      <ligandPart>
        <name>N(6)-methyladenosine 5'-phosphate residue</name>
        <dbReference type="ChEBI" id="CHEBI:74449"/>
      </ligandPart>
    </feature>
    <feature type="binding site" evidence="2">
      <location>
        <position position="1310"/>
      </location>
      <ligand>
        <name>RNA</name>
        <dbReference type="ChEBI" id="CHEBI:33697"/>
      </ligand>
      <ligandPart>
        <name>N(6)-methyladenosine 5'-phosphate residue</name>
        <dbReference type="ChEBI" id="CHEBI:74449"/>
      </ligandPart>
    </feature>
    <feature type="binding site" evidence="2">
      <location>
        <position position="1360"/>
      </location>
      <ligand>
        <name>RNA</name>
        <dbReference type="ChEBI" id="CHEBI:33697"/>
      </ligand>
      <ligandPart>
        <name>N(6)-methyladenosine 5'-phosphate residue</name>
        <dbReference type="ChEBI" id="CHEBI:74449"/>
      </ligandPart>
    </feature>

RDF format

We have made the following changes to the UniProt RDF schema ontology to standardize the description of a ligand, and optionally the bound part of the ligand, with the ChEBI ontology.

• We have deprecated the classes Calcium_Binding_Annotation, Metal_Binding_Annotation and NP_Binding_Annotation.
• We have introduced two new properties, ligand and ligandPart, whose rdfs:domain is the Binding_Site_Annotation class. The nature of a ligand or ligand part is described as one of:
  • an rdfs:subClassOf of the corresponding ChEBI class (when a ChEBI identifier is available)
  • a class identified by an entry URI fragment whose identifier is generated from the ligand (part) name (when no ChEBI identifier is available)
• A partOf statement is used to link a ligand part class to the ligand class that contains the part. As a consequence, the partOf property will loose its rdfs:domain and rdfs:range.
• The label and note of a ligand (LigandLabel, LigandNote) or ligand part (LigandPartLabel, LigandPartNote) are described at the corresponding class level with rdfs:label and rdfs:comment statements, respectively.
• The representation of the annotation Note and the Evidences remains unchanged.

In the examples below, the parts of the annotation whose structure has not changed (details of sequence range, evidences) are omitted.

Example: Q9H5X1

Previous format:

<Q9H5X1> rdf:type up:Protein ;
...
  up:annotation ...
    <Q9H5X1#SIP205C589B1B82C19D> ,
    <Q9H5X1#SIP0FDA08578DA645F1> ,
    <Q9H5X1#SIPF931DC9BFE3EE1EA> ,
    <Q9H5X1#SIP9FE49AAED1489740> ,
...
<Q9H5X1#SIP205C589B1B82C19D>
  rdf:type up:Metal_Binding_Annotation ;
  rdfs:comment "Zinc 1; shared with dimeric partner" ;
  up:range range:22862455408963886tt89tt89 .
...
<Q9H5X1#SIP0FDA08578DA645F1>
  rdf:type up:Metal_Binding_Annotation ;
  rdfs:comment "Zinc 2; shared with dimeric partner" ;
  up:range range:22862455408963886tt89tt89 .
<Q9H5X1#SIPF931DC9BFE3EE1EA>
  rdf:type up:Metal_Binding_Annotation ;
  rdfs:comment "Zinc 1; shared with dimeric partner" ;
  up:range range:22862455408963886tt123tt123 .
...
<Q9H5X1#SIP9FE49AAED1489740>
  rdf:type up:Metal_Binding_Annotation ;
  rdfs:comment "Zinc 2; shared with dimeric partner" ;
  up:range range:22862455408963886tt123tt123 .

New format:

<Q9H5X1> rdf:type up:Protein ;
...
  up:annotation ...
    <Q9H5X1#SIPEF929039F510ECEF> ,
    <Q9H5X1#SIP920EDE1AF7D0C789> ,
    <Q9H5X1#SIP72E42A3FB2BD4B9A> ,
    <Q9H5X1#SIP34635D3021CE14FA> ,
...
<Q9H5X1#SIPEF929039F510ECEF>
  rdf:type up:Binding_Site_Annotation ;
  up:ligand <Q9H5X1#SIPA9D42F70EC978DA2> ;
  up:range range:22862455408963886tt89tt89 .
...
<Q9H5X1#SIP920EDE1AF7D0C789>
  rdf:type up:Binding_Site_Annotation ;
  up:ligand <Q9H5X1#SIP2113E97BF945072A> ;
  up:range range:22862455408963886tt89tt89 .
<Q9H5X1#SIP72E42A3FB2BD4B9A>
  rdf:type up:Binding_Site_Annotation ;
  up:ligand <Q9H5X1#SIPA9D42F70EC978DA2> ;
  up:range range:22862455408963886tt123tt123 .
...
<Q9H5X1#SIP34635D3021CE14FA>
  rdf:type up:Binding_Site_Annotation ;
  up:ligand <Q9H5X1#SIP2113E97BF945072A> ;
  up:range range:22862455408963886tt123tt123 .
...
<Q9H5X1#SIPA9D42F70EC978DA2>
  rdfs:subClassOf <http://purl.obolibrary.org/obo/CHEBI_29105> ;
  rdfs:label "1" ;
  rdfs:comment "ligand shared between dimeric partners" .
<Q9H5X1#SIP2113E97BF945072A>
  rdfs:subClassOf <http://purl.obolibrary.org/obo/CHEBI_29105> ;
  rdfs:label "2" ;
  rdfs:comment "ligand shared between dimeric partners" .

Example: P39186

Previous format:

<P39186> rdf:type up:Protein ;
...
  up:annotation ...
    <P39186#SIP2FA351DB0B3C2F16> ,
    <P39186#SIP68C53D2ADFC188FB> ,
    <P39186#SIP293BA29AFBE6705D> ,
    <P39186#SIP04086D3B0200EFDB> ,
    <P39186#SIP421DBD60EE668E9A> ,
    <P39186#SIPBE78F7D7D1DFDB96> ,
    <P39186#SIPF42DD8F9E97D4C04> ,
    <P39186#SIP67D0B11099583DF4> ,
...
<P39186#SIP2FA351DB0B3C2F16>
  rdf:type up:Metal_Binding_Annotation ;
  rdfs:comment "Iron (heme C 1 axial ligand); via tele nitrogen" ;
  up:range range:22574318868772398tt79tt79 .
...
<P39186#SIP68C53D2ADFC188FB>
  rdf:type up:Metal_Binding_Annotation ;
  rdfs:comment "Iron (heme C 1 axial ligand); via tele nitrogen" ;
  up:range range:22574318868772398tt97tt97 .
...
<P39186#SIP293BA29AFBE6705D>
  rdf:type up:Metal_Binding_Annotation ;
  rdfs:comment "Iron (heme C 2 axial ligand); via tele nitrogen" ;
  up:range range:22574318868772398tt114tt114 .
...
<P39186#SIP04086D3B0200EFDB>
  rdf:type up:Metal_Binding_Annotation ;
  rdfs:comment "Iron (heme C 2 axial ligand); via tele nitrogen" ;
  up:range range:22574318868772398tt137tt137 .
...
<P39186#SIP421DBD60EE668E9A>
  rdf:type up:Binding_Site_Annotation ;
  rdfs:comment "Heme C 1; covalent" ;
  up:range range:22574318868772398tt93tt93 .
...
<P39186#SIPBE78F7D7D1DFDB96>
  rdf:type up:Binding_Site_Annotation ;
  rdfs:comment "Heme C 1; covalent" ;
  up:range range:22574318868772398tt96tt96 .
...
<P39186#SIPF42DD8F9E97D4C04>
  rdf:type up:Binding_Site_Annotation ;
  rdfs:comment "Heme C 2; covalent" ;
  up:range range:22574318868772398tt133tt133 .
...
<P39186#SIP67D0B11099583DF4>
  rdf:type up:Binding_Site_Annotation ;
  rdfs:comment "Heme C 2; covalent" ;
  up:range range:22574318868772398tt136tt136 .

New format:

<P39186> rdf:type up:Protein ;
...
  up:annotation ...
    <P39186#SIP6B05083539025B03> ,
    <P39186#SIP26EC788A934C8F47> ,
    <P39186#SIPE6A28D6EA4C9FD5D> ,
    <P39186#SIPFBD274DC3C6C2D4D> ,
    <P39186#SIP35F10B423DCD5ABF> ,
    <P39186#SIP2B84A319ABAB6D10> ,
    <P39186#SIP3DF7879BD48FFB15> ,
    <P39186#SIP4B946529653D1444> ,
...
<P39186#SIP6B05083539025B03>
  rdf:type up:Binding_Site_Annotation ;
  rdfs:comment "axial binding residue" ;
  up:ligand <P39186#SIP03157F908F4B7F18> ;
  up:ligandPart <P39186#SIP85C37483D3E0B42A> ;
  up:range range:22574318868772398tt79tt79 .
...
<P39186#SIP26EC788A934C8F47>
  rdf:type up:Binding_Site_Annotation ;
  rdfs:comment "covalent" ;
  up:ligand <P39186#SIP03157F908F4B7F18> ;
  up:range range:22574318868772398tt93tt93 .
...
<P39186#SIPE6A28D6EA4C9FD5D>
  rdf:type up:Binding_Site_Annotation ;
  rdfs:comment "covalent" ;
  up:ligand <P39186#SIP03157F908F4B7F18> ;
  up:range range:22574318868772398tt96tt96 .
...
<P39186#SIPFBD274DC3C6C2D4D>
  rdf:type up:Binding_Site_Annotation ;
  rdfs:comment "axial binding residue" ;
  up:ligand <P39186#SIP03157F908F4B7F18> ;
  up:ligandPart <P39186#SIP85C37483D3E0B42A> ;
  up:range range:22574318868772398tt97tt97 .
...
<P39186#SIP35F10B423DCD5ABF>
  rdf:type up:Binding_Site_Annotation ;
  rdfs:comment "axial binding residue" ;
  up:ligand <P39186#SIP997F95171519AEFE> ;
  up:ligandPart <P39186#SIP428C6123B1B272B9> ;
  up:range range:22574318868772398tt114tt114 .
...
<P39186#SIP2B84A319ABAB6D10>
  rdf:type up:Binding_Site_Annotation ;
  rdfs:comment "covalent" ;
  up:ligand <P39186#SIP997F95171519AEFE> ;
  up:range range:22574318868772398tt133tt133 .
...
<P39186#SIP3DF7879BD48FFB15>
  rdf:type up:Binding_Site_Annotation ;
  rdfs:comment "covalent" ;
  up:ligand <P39186#SIP997F95171519AEFE> ;
  up:range range:22574318868772398tt136tt136 .
...
<P39186#SIP4B946529653D1444>
  rdf:type up:Binding_Site_Annotation ;
  rdfs:comment "axial binding residue" ;
  up:ligand <P39186#SIP997F95171519AEFE> ;
  up:ligandPart <P39186#SIP428C6123B1B272B9> ;
  up:range range:22574318868772398tt137tt137 .
...
<P39186#SIP03157F908F4B7F18>
  rdfs:subClassOf <http://purl.obolibrary.org/obo/CHEBI_61717> ;
  rdfs:label "1" .
<P39186#SIP85C37483D3E0B42A>
  rdfs:subClassOf <http://purl.obolibrary.org/obo/CHEBI_18248> ;
  up:partOf <P39186#SIP03157F908F4B7F18> .
<P39186#SIP997F95171519AEFE>
  rdfs:subClassOf <http://purl.obolibrary.org/obo/CHEBI_61717> ;
  rdfs:label "2" .
<P39186#SIP428C6123B1B272B9>
  rdfs:subClassOf <http://purl.obolibrary.org/obo/CHEBI_18248> ;
  up:partOf <P39186#SIP997F95171519AEFE> .

Example: Q9H6S0

Previous format:

<Q9H6S0> rdf:type up:Protein ;
...
  up:annotation ...
    <Q9H6S0#SIP1A82C4FF56746BB8> ,
...
    <Q9H6S0#SIPBD815A286DC38CC5> ,
    <Q9H6S0#SIPC5465EB9289C0B15> ,
...
<Q9H6S0#SIP1A82C4FF56746BB8>
  rdf:type up:Region_Annotation ;
  rdfs:comment "N6-methyladenosine residue binding" ;
  up:range range:22862455425413166tt1294tt1296 .
...
<Q9H6S0#SIPBD815A286DC38CC5>
  rdf:type up:Binding_Site_Annotation ;
  rdfs:comment "N6-methyladenosine residue" ;
  up:range range:22862455425413166tt1310tt1310 .
...
<Q9H6S0#SIPC5465EB9289C0B15>
  rdf:type up:Binding_Site_Annotation ;
  rdfs:comment "N6-methyladenosine residue" ;
  up:range range:22862455425413166tt1360tt1360 .

New format:

<Q9H6S0> rdf:type up:Protein ;
...
  up:annotation ...
    <Q9H6S0#SIP422D37614A6D5721> ,
    <Q9H6S0#SIP181E7990DC5C18D8> ,
    <Q9H6S0#SIP21050F3BB73E81A2> ,
...
<Q9H6S0#SIP422D37614A6D5721>
  rdf:type up:Binding_Site_Annotation ;
  up:ligand <Q9H6S0#SIPC276DB5E970331C9> ;
  up:ligandPart <Q9H6S0#SIP93E43149D18FF63B> ;
  up:range range:22862455425413166tt1294tt1296 .
...
<Q9H6S0#SIP181E7990DC5C18D8>
  rdf:type up:Binding_Site_Annotation ;
  up:ligand <Q9H6S0#SIPC276DB5E970331C9> ;
  up:ligandPart <Q9H6S0#SIP93E43149D18FF63B> ;
  up:range range:22862455425413166tt1310tt1310 .
...
<Q9H6S0#SIP21050F3BB73E81A2>
  rdf:type up:Binding_Site_Annotation ;
  up:ligand <Q9H6S0#SIPC276DB5E970331C9> ;
  up:ligandPart <Q9H6S0#SIP93E43149D18FF63B> ;
  up:range range:22862455425413166tt1360tt1360 .
...
<Q9H6S0#SIPC276DB5E970331C9>
  rdfs:subClassOf <http://purl.obolibrary.org/obo/CHEBI_33697> .
<Q9H6S0#SIP93E43149D18FF63B>
  rdfs:subClassOf <http://purl.obolibrary.org/obo/CHEBI_74449> ;
  up:partOf <Q9H6S0#SIPC276DB5E970331C9> .

Changes to the controlled vocabulary of human diseases

New diseases:

• Agammaglobulinemia 9, autosomal recessive
• Agammaglobulinemia 10, autosomal dominant
• Anemia, congenital dyserythropoietic, 3A
• Anemia, congenital dyserythropoietic, 3B, autosomal recessive
• Brunet-Wagner neurodevelopmental syndrome
• Bryant-Li-Bhoj neurodevelopmental syndrome 1
• Bryant-Li-Bhoj neurodevelopmental syndrome 2
• Cardiomyopathy, dilated 2F
• Cerebellar dysfunction, impaired intellectual development, and hypogonadotropic hypogonadism
• Charcot-Marie-Tooth disease, demyelinating, 1I
• Charcot-Marie-Tooth disease, demyelinating, 1H
• Combined oxidative phosphorylation deficiency 54
• Combined oxidative phosphorylation deficiency 55
• Congenital disorder of deglycosylation 2
• Congenital disorder of glycosylation 1W, autosomal dominant
• Craniofacial microsomia
• Craniotubular dysplasia, Ikegawa type
• Deafness, autosomal dominant, 82
• Developmental and epileptic encephalopathy 100
• Developmental and epileptic encephalopathy 101
• Developmental delay with variable neurologic and brain abnormalities
• Dystonia 33
• Dystonia 34, myoclonic
• Dystonia, early-onset, and/or spastic paraplegia
• Epidermolysis bullosa, junctional 2A, intermediate
• Epidermolysis bullosa, junctional 2B, severe
• Epidermolysis bullosa, junctional 3A, intermediate
• Epidermolysis bullosa, junctional 3B, severe
• Epidermolysis bullosa, junctional 4, intermediate
• Epidermolysis bullosa, junctional 5A, intermediate
• Epidermolysis bullosa, junctional 6, with pyloric atresia
• Ferguson-Bonni neurodevelopmental syndrome
• Gastrointestinal defects and immunodeficiency syndrome 2
• Hyper-IgE recurrent infection syndrome 4A, autosomal dominant
• Hypogonadotropic hypogonadism 26 with or without anosmia
• Hypogonadotropic hypogonadism 27 without anosmia
• Immunodeficiency 93 and hypertrophic cardiomyopathy
• Immunodeficiency 94 with autoinflammation and dysmorphic facies
• Immunodeficiency 95
• Immunodeficiency 96
• Inclusion body myopathy and brain white matter abnormalities
• Intellectual developmental disorder, autosomal recessive 73
• Intellectual developmental disorder, FRA12A type
• Intellectual disability and myopathy syndrome
• Kury-Isidor syndrome
• Leukoencephalopathy, hereditary diffuse, with spheroids 2
• Leukodystrophy, hypomyelinating, 23, with ataxia, deafness, liver dysfunction, and dilated cardiomyopathy
• Macrocephaly, neurodevelopmental delay, lymphoid hyperplasia, and persistent fetal hemoglobin
• Mitochondrial DNA depletion syndrome 20, MNGIE type
• Mucopolysaccharidosis 10
• Myopia 28, autosomal recessive
• Neurodevelopmental disorder with central hypotonia and dysmorphic facies
• Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis
• Neurodevelopmental disorder with or without variable movement or behavioral abnormalities
• Noonan syndrome 14
• Oculopharyngodistal myopathy 4
• Oocyte maturation defect 12
• Osteogenesis imperfecta 22
• Parkinsonism-dystonia 3, childhood-onset
• Pulmonary fibrosis, and/or bone marrow failure, telomere-related, 6
• Rauch-Steindl syndrome
• Restrictive dermopathy 2
• Rod-cone dystrophy, sensorineural deafness, and Fanconi-type renal dysfunction
• Spastic paraplegia 85, autosomal recessive
• Spastic paraplegia 86, autosomal recessive
• Spermatogenic failure 64
• Spermatogenic failure 65
• Spermatogenic failure 66
• Spermatogenic failure 67
• Spermatogenic failure 68
• Stuve-Wiedemann syndrome 2
• Teebi hypertelorism syndrome 2
• Tessadori-van Haaften neurodevelopmental syndrome 1
• Tessadori-van Haaften neurodevelopmental syndrome 2
• Thrombophilia 13, X-linked, due to factor VIII defect
• Trichothiodystrophy 8, non-photosensitive
• Trichothiodystrophy 9, non-photosensitive
• Yoon-Bellen neurodevelopmental syndrome

Modified diseases:

• Alacrima, achalasia, and mental retardation syndrome -> Alacrima, achalasia, and intellectual disability syndrome
• Alopecia-mental retardation syndrome 1 -> Alopecia-intellectual disability syndrome 1
• Alpha-thalassemia mental retardation syndrome, X-linked -> Alpha-thalassemia/intellectual disability syndrome, X-linked
• Alport syndrome with mental retardation, midface hypoplasia and elliptocytosis -> AMME complex
• Arthrogryposis, mental retardation, and seizures -> Arthrogryposis, intellectual disability, and seizures
• Brody myopathy -> Brody disease
• Cerebellar ataxia, mental retardation, and dysequilibrium syndrome 1 -> Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1
• Cerebellar ataxia, mental retardation, and dysequilibrium syndrome 2 -> Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 2
• Cerebellar ataxia, mental retardation, and dysequilibrium syndrome 3 -> Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 3
• Cerebellar ataxia, mental retardation, and dysequilibrium syndrome 4 -> Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4
• Cerebellar ataxia, non-progressive, with mental retardation -> Cerebellar dysfunction with variable cognitive and behavioral abnormalities
• Cleft palate, cardiac defects, and mental retardation -> Cleft palate, cardiac defects, and intellectual disability
• Coloboma, congenital heart disease, ichthyosiform dermatosis, mental retardation and ear anomalies syndrome -> Coloboma, congenital heart disease, ichthyosiform dermatosis, intellectual disability and ear anomalies syndrome
• Coloboma, ocular, with or without hearing impairment, cleft lip/palate, and/or mental retardation -> Coloboma, ocular, with or without hearing impairment, cleft lip/palate, and/or intellectual disability
• Congenital central hypoventilation syndrome -> Central hypoventilation syndrome, congenital, 1
• Congenital disorder of deglycosylation -> Congenital disorder of deglycosylation 1
• Craniofacial dysmorphism, skeletal anomalies and mental retardation syndrome -> Craniofacial dysmorphism, skeletal anomalies and intellectual disability syndrome
• Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures syndrome -> Deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures syndrome
• Develomental and epileptic encephalopathy 94 -> Developmental and epileptic encephalopathy 94
• Epidermolysis bullosa simplex, with migratory circinate erythema -> Epidermolysis bullosa simplex 2E, with migratory circinate erythema
• Epidermolysis bullosa simplex, with mottled pigmentation -> Epidermolysis bullosa simplex 2F, with mottled pigmentation
• Epilepsy, hearing loss, and mental retardation syndrome -> Neurodevelopmental disorder with hearing loss, seizures, and brain abnormalities
• Gastrointestinal defects and immunodeficiency syndrome -> Gastrointestinal defects and immunodeficiency syndrome 1
• Hyperphosphatasia with mental retardation syndrome 1 -> Hyperphosphatasia with intellectual disability syndrome 1
• Hyperphosphatasia with mental retardation syndrome 2 -> Hyperphosphatasia with intellectual disability syndrome 2
• Hyperphosphatasia with mental retardation syndrome 3 -> Hyperphosphatasia with intellectual disability syndrome 3
• Hyperphosphatasia with mental retardation syndrome 4 -> Hyperphosphatasia with intellectual disability syndrome 4
• Hyperphosphatasia with mental retardation syndrome 6 -> Hyperphosphatasia with intellectual disability syndrome 6
• Hypomagnesemia, seizures, and mental retardation 1 -> Hypomagnesemia, seizures, and intellectual disability 1
• Hypomagnesemia, seizures, and mental retardation 2 -> Hypomagnesemia, seizures, and intellectual disability 2
• Ichthyosis, spastic quadriplegia, and mental retardation -> Ichthyosis, spastic quadriplegia, and intellectual disability
• Leukoencephalopathy, diffuse hereditary, with spheroids -> Leukoencephalopathy, hereditary diffuse, with spheroids 1
• Mental retardation, anterior maxillary protrusion, and strabismus -> Intellectual disability, anterior maxillary protrusion, and strabismus
• Mental retardation, aphasia, shuffling gait, and adducted thumbs syndrome -> MASA syndrome
• Mental retardation, autosomal dominant 1 -> Intellectual developmental disorder, autosomal dominant 1
• Mental retardation, autosomal dominant 10 -> Intellectual developmental disorder, autosomal dominant 10
• Mental retardation, autosomal dominant 13 -> Intellectual developmental disorder, autosomal dominant 13
• Mental retardation, autosomal dominant 2 -> Intellectual developmental disorder, autosomal dominant 2
• Mental retardation, autosomal dominant 20 -> Neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language
• Mental retardation, autosomal dominant 21 -> Intellectual developmental disorder, autosomal dominant 21
• Mental retardation, autosomal dominant 22 -> Intellectual developmental disorder, autosomal dominant 22
• Mental retardation, autosomal dominant 23 -> Intellectual developmental disorder, autosomal dominant 23
• Mental retardation, autosomal dominant 26 -> Intellectual developmental disorder, autosomal dominant 26
• Mental retardation, autosomal dominant 29 -> Intellectual developmental disorder, autosomal dominant 29
• Mental retardation, autosomal dominant 3 -> Intellectual developmental disorder, autosomal dominant 3
• Mental retardation, autosomal dominant 30 -> Intellectual developmental disorder, autosomal dominant 30
• Mental retardation, autosomal dominant 33 -> Intellectual developmental disorder, autosomal dominant 33
• Mental retardation, autosomal dominant 34 -> Intellectual developmental disorder, autosomal dominant 34
• Mental retardation, autosomal dominant 35 -> Intellectual developmental disorder, autosomal dominant 35
• Mental retardation, autosomal dominant 36 -> Intellectual developmental disorder, autosomal dominant 36
• Mental retardation, autosomal dominant 38 -> Intellectual developmental disorder, autosomal dominant 38
• Mental retardation, autosomal dominant 4 -> Intellectual developmental disorder, autosomal dominant 4
• Mental retardation, autosomal dominant 40 -> Intellectual developmental disorder, autosomal dominant 40
• Mental retardation, autosomal dominant 41 -> Intellectual developmental disorder, autosomal dominant 41
• Mental retardation, autosomal dominant 43 -> Intellectual developmental disorder, autosomal dominant 43
• Mental retardation, autosomal dominant 45 -> Intellectual developmental disorder, autosomal dominant 45
• Mental retardation, autosomal dominant 46 -> Intellectual developmental disorder, autosomal dominant 46
• Mental retardation, autosomal dominant 47 -> Intellectual developmental disorder, autosomal dominant 47
• Mental retardation, autosomal dominant 48 -> Intellectual developmental disorder, autosomal dominant 48
• Mental retardation, autosomal dominant 5 -> Intellectual developmental disorder, autosomal dominant 5
• Mental retardation, autosomal dominant 51 -> Intellectual developmental disorder, autosomal dominant 51
• Mental retardation, autosomal dominant 52 -> Intellectual developmental disorder, autosomal dominant 52
• Mental retardation, autosomal dominant 53 -> Intellectual developmental disorder, autosomal dominant 53
• Mental retardation, autosomal dominant 54 -> Intellectual developmental disorder, autosomal dominant 54
• Mental retardation, autosomal dominant 57 -> Intellectual developmental disorder, autosomal dominant 57
• Mental retardation, autosomal dominant 58 -> Intellectual developmental disorder, autosomal dominant 58
• Mental retardation, autosomal dominant 6, with or without seizures -> Intellectual developmental disorder, autosomal dominant 6, with or without seizures
• Mental retardation, autosomal dominant 7 -> Intellectual developmental disorder, autosomal dominant 7
• Mental retardation, autosomal recessive 1 -> Intellectual developmental disorder, autosomal recessive 1
• Mental retardation, autosomal recessive 13 -> Intellectual developmental disorder, autosomal recessive 13
• Mental retardation, autosomal recessive 14 -> Intellectual developmental disorder, autosomal recessive 14
• Mental retardation, autosomal recessive 2A -> Intellectual developmental disorder, autosomal recessive 2
• Mental retardation, autosomal recessive 3 -> Intellectual developmental disorder, autosomal recessive 3
• Mental retardation, autosomal recessive 34, with variant lissencephaly -> Intellectual developmental disorder, autosomal recessive 34, with variant lissencephaly
• Mental retardation, autosomal recessive 36 -> Neurodevelopmental disorder with brain abnormalities, poor growth, and dysmorphic facies
• Mental retardation, autosomal recessive 37 -> Intellectual developmental disorder, autosomal recessive 37
• Mental retardation, autosomal recessive 38 -> Intellectual developmental disorder, autosomal recessive 38
• Mental retardation, autosomal recessive 40 -> Neurodevelopmental disorder with feeding difficulties, thin corpus callosum, and foot deformity
• Mental retardation, autosomal recessive 41 -> Intellectual developmental disorder, autosomal recessive 41
• Mental retardation, autosomal recessive 42 -> Neurodevelopmental disorder with dysmorphic features, spasticity, and brain abnormalities
• Mental retardation, autosomal recessive 44 -> Intellectual developmental disorder, autosomal recessive 44
• Mental retardation, autosomal recessive 45 -> Intellectual developmental disorder, autosomal recessive 45
• Mental retardation, autosomal recessive 46 -> Intellectual developmental disorder, autosomal recessive 46
• Mental retardation, autosomal recessive 47 -> Intellectual developmental disorder, autosomal recessive 47
• Mental retardation, autosomal recessive 48 -> Intellectual developmental disorder, autosomal recessive 48
• Mental retardation, autosomal recessive 5 -> Intellectual developmental disorder, autosomal recessive 5
• Mental retardation, autosomal recessive 50 -> Intellectual developmental disorder, autosomal recessive 50
• Mental retardation, autosomal recessive 51 -> Intellectual developmental disorder, autosomal recessive 51
• Mental retardation, autosomal recessive 52 -> Intellectual developmental disorder, autosomal recessive 52
• Mental retardation, autosomal recessive 54 -> Intellectual developmental disorder, autosomal recessive 54
• Mental retardation, autosomal recessive 56 -> Intellectual developmental disorder, autosomal recessive 56
• Mental retardation, autosomal recessive 59 -> Intellectual developmental disorder, autosomal recessive 59
• Mental retardation, autosomal recessive 60 -> Intellectual developmental disorder, autosomal recessive 60
• Mental retardation, autosomal recessive 61 -> Intellectual developmental disorder, autosomal recessive 61
• Mental retardation, autosomal recessive 63 -> Intellectual developmental disorder, autosomal recessive 63
• Mental retardation, autosomal recessive 64 -> Intellectual developmental disorder, autosomal recessive 64
• Mental retardation, autosomal recessive 65 -> Intellectual developmental disorder, autosomal recessive 65
• Mental retardation, autosomal recessive 66 -> Intellectual developmental disorder, autosomal recessive 66
• Mental retardation, autosomal recessive 7 -> Intellectual developmental disorder, autosomal recessive 7
• Mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma -> Intellectual disability, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma
• Mental retardation, truncal obesity, retinal dystrophy, and micropenis -> Intellectual disability, truncal obesity, retinal dystrophy, and micropenis
• Mental retardation, X-linked 3 -> Methylmalonic aciduria and homocystinuria, cblX type
• Mental retardation, X-linked 45 -> Intellectual developmental disorder, X-linked 45
• Mental retardation, X-linked 46 -> Intellectual developmental disorder, X-linked 46
• Mental retardation, X-linked 88 -> Intellectual developmental disorder, X-linked 88
• Mental retardation, X-linked 89 -> Intellectual developmental disorder, X-linked 89
• Mental retardation, X-linked 91 -> Intellectual developmental disorder, X-linked 91
• Mental retardation, X-linked 92 -> Intellectual developmental disorder, X-linked 92
• Mental retardation, X-linked 95 -> Intellectual developmental disorder, X-linked 95
• Mental retardation, X-linked, syndromic, Martin-Probst type -> Martin-Probst syndrome
• Mental retardation-hypotonic facies syndrome, X-linked, 1 -> Intellectual disability-hypotonic facies syndrome, X-linked, 1
• Mental retardation with language impairment and autistic features -> Intellectual disability with language impairment and autistic features
• Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation -> Microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability
• Myopia 27 -> Myopia 27, autosomal dominant
• Nephrolithiasis 1 -> Nephrolithiasis, X-linked recessive, with renal failure
• Nephrolithiasis 2 -> Dent disease 1
• Optic atrophy 10 with or without ataxia, mental retardation, and seizures -> Optic atrophy 10 with or without ataxia, intellectual disability, and seizures
• Parkinsonism-dystonia infantile -> Parkinsonism-dystonia 1, infantile-onset
• Parkinsonism-dystonia, infantile, 2 -> Parkinsonism-dystonia 2, infantile-onset
• Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis -> Neurodevelopmental disorder with spasticity, hypomyelinating leukodystrophy, and brain abnormalities
• Renal tubular acidosis, proximal, with ocular abnormalities and mental retardation -> Renal tubular acidosis, proximal, with ocular abnormalities and intellectual disability
• Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance -> Seizures, sensorineural deafness, ataxia, intellectual disability, and electrolyte imbalance
• Skeletal defects, genital hypoplasia, and mental retardation -> Skeletal defects, genital hypoplasia, and impaired intellectual development
• Sotos syndrome 1 -> Sotos syndrome
• Sotos syndrome 2 -> Malan syndrome
• Sotos syndrome 3 -> Intellectual developmental disorder, autosomal recessive 74
• Spastic paraplegia 49, autosomal recessive -> Neuropathy, hereditary sensory and autonomic, 9, with developmental delay
• Stueve-Wiedemann syndrome -> Stuve-Wiedemann syndrome
• Teebi hypertelorism syndrome -> Teebi hypertelorism syndrome 1

Deleted diseases

• Brachydactyly-mental retardation syndrome
• Neuropathy, hereditary, with or without age-related macular degeneration
• Opitz GBBB syndrome 2

Changes to the controlled vocabulary for PTMs

New term for the feature key 'Cross-link' ('CROSSLNK' in the flat file):

• Dityrosine (Tyr-Tyr) (interchain with Y-...)

New term for the feature key 'Modified residue' ('MOD_RES' in the flat file):

• ADP-ribosylhistidine

Changes to keywords

Modified keyword:

• Mental retardation -> Intellectual disability

Headline

Prenylation for antiviral activity

We are not equal before viral infections. Take SARS-CoV-2 and COVID-19. During the pandemic the severity of the disease ranged from no symptoms at all to death, for at least 15 million individuals. Many factors can contribute to these differences, from environmental, such as deficiencies in diet, exercise, or sleep, to genetic ones, such as those contributing to the efficiency of the type I interferon response. Among the latter, 2'-5'-oligoadenylate synthase 1 (OAS1) has been the focus of several recent studies.

OAS1 is a sensor of viral double-stranded RNA (dsRNA). Binding to dsRNA induces a conformational change in OAS1 and its activation. Activated OAS1 catalyzes the polymerization of adenosine triphosphate (ATP) into a second messenger, 2'-5'-oligoadenylate (2'-5'A), which then binds monomeric ribonuclease L (RNase L) leading to its dimerization and subsequent activation. RNase L degrades cellular and viral RNA and blocks viral replication. OAS1 is expressed in the respiratory tract, a location perfectly suited to protect from SARS-CoV-2 infections, and binds two conserved stem loops in SARS-CoV-2 5'-untranslated region (UTR) with great specificity.

But there is more to it. OAS1 gene encodes at least 4 different proteins generated by alternative splicing. The predominant isoforms, called p46 and p42, have a common catalytic activity, but differ in the inclusion of the terminal exon, where a prenylation site is encoded. Contrary to p42, p46 is geranylgeranylated and this makes a great deal of difference. In cultured cells, only p46, not p42, can inhibit SARS-CoV-2, unless a prenylation site is engineered into p42, suggesting that targeting to membranes is crucial for OAS1 effectiveness. Preliminary clinical investigations also show that COVID-19 patients who do not express p46 are statistically more likely to develop severe COVID-19, i.e., to be admitted to the intensive care unit.

The explanation may lie in the fact that positive-strand RNA viruses, such as flaviviruses, picornaviruses, and coronaviruses, including SARS-CoV-2, replicate their RNA within modified host organelles of the endomembrane system. Membrane-bound OAS1 colocalizes with these organelles, where it can ideally detect viral RNAs and initiate their destruction. In support of this hypothesis, OAS1 effectiveness was demonstrated not only against SARS-CoV-2, but also against other viruses that form replicative organelles, while there was no inhibition of other respiratory RNA viruses, such as human parainfluenza virus type 3 and human respiratory syncytial virus, which do not use this type of vesicle.

The alternative splicing event which leads to p46 production and efficient antiviral response hangs by a thread, or rather by a single nucleotide variation within the last OAS1 intron, A>G (rs10774671). The presence of G at this location creates a splice acceptor site, allowing the inclusion of the last exon, hence that of the crucial prenylation site, while in the presence of A, the last exon is skipped. Unfortunately, the A allele is the major one in the overall human population with a frequency of 66%, although in some ethnic groups the prevalence of the G allele is higher, in people of African ancestry, for instance, its frequency is about 58%. Fortunately, prenylated OAS1 is likely only one of multiple interferon-stimulated genes that mediate the inhibition of SARS-CoV-2.

As of this release, the updated OAS1 entry is publicly available in UniProtKB/Swiss-Prot.

UniProtKB news

Cross-references to AlphaFoldDB

Cross-references have been added to AlphaFoldDB, a database of protein structure predictions for the human proteome and other key proteins of interest.

AlphaFoldDB is available at https://alphafold.ebi.ac.uk/.

The format of the explicit links is:

Resource abbreviation	AlphaFoldDB
Resource identifier	UniProtKB accession number

Example: P41182

Show all entries having a cross-reference to AlphaFoldDB.

Text format

Example: P41182

DR   AlphaFoldDB; P41182; -.

XML format

Example: P41182

<dbReference type="AlphaFoldDB" id="P41182"/>

RDF format

Example: P41182

uniprot:P41182
  rdfs:seeAlso <http://purl.uniprot.org/alphafolddb/P41182> .
<http://purl.uniprot.org/alphafolddb/P41182>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/AlphaFoldDB> .

Version numbers for identifiers in Ensembl cross-references

In UniProtKB cross-references to Ensembl, we are now using version numbers for Ensembl identifiers wherever possible.

Text format

Example: A6NEM1

Previous format:

DR   Ensembl; ENST00000618348; ENSP00000481078; ENSG00000197978.
DR   Ensembl; ENST00000620574; ENSP00000479589; ENSG00000274320.

New format:

DR   Ensembl; ENST00000618348.2; ENSP00000481078.1; ENSG00000197978.10.
DR   Ensembl; ENST00000620574.2; ENSP00000479589.1; ENSG00000274320.2.

XML format

Example: A6NEM1

Previous format:

<dbReference type="Ensembl" id="ENST00000618348">
  <property type="protein sequence ID" value="ENSP00000481078"/>
  <property type="gene ID" value="ENSG00000197978"/>
</dbReference>
<dbReference type="Ensembl" id="ENST00000620574">
  <property type="protein sequence ID" value="ENSP00000479589"/>
  <property type="gene ID" value="ENSG00000274320"/>
</dbReference>

New format:

<dbReference type="Ensembl" id="ENST00000618348.2">
  <property type="protein sequence ID" value="ENSP00000481078.1"/>
  <property type="gene ID" value="ENSG00000197978.10"/>
</dbReference>
<dbReference type="Ensembl" id="ENST00000620574.2">
  <property type="protein sequence ID" value="ENSP00000479589.1"/>
  <property type="gene ID" value="ENSG00000274320.2"/>
</dbReference>

RDF format

Example: A6NEM1

Previous format:

uniprot:A6NEM1
  rdfs:seeAlso <http://rdf.ebi.ac.uk/resource/ensembl.transcript/ENST00000618348> ,
               <http://rdf.ebi.ac.uk/resource/ensembl.transcript/ENST00000620574> .
<http://rdf.ebi.ac.uk/resource/ensembl.transcript/ENST00000618348>
  rdf:type up:Transcript_Resource ;
  up:database <http://purl.uniprot.org/database/Ensembl> ;
  up:translatedTo <http://rdf.ebi.ac.uk/resource/ensembl.protein/ENSP00000481078> ;
  up:transcribedFrom <http://rdf.ebi.ac.uk/resource/ensembl/ENSG00000197978> .
<http://rdf.ebi.ac.uk/resource/ensembl.transcript/ENST00000620574>
  rdf:type up:Transcript_Resource ;
  up:database <http://purl.uniprot.org/database/Ensembl> ;
  up:translatedTo <http://rdf.ebi.ac.uk/resource/ensembl.protein/ENSP00000479589> ;
  up:transcribedFrom <http://rdf.ebi.ac.uk/resource/ensembl/ENSG00000274320> .

New format:

uniprot:A6NEM1
  rdfs:seeAlso <http://rdf.ebi.ac.uk/resource/ensembl.transcript/ENST00000618348.2> ,
               <http://rdf.ebi.ac.uk/resource/ensembl.transcript/ENST00000620574.2> .
<http://rdf.ebi.ac.uk/resource/ensembl.transcript/ENST00000618348.2>
  rdf:type up:Transcript_Resource ;
  up:database <http://purl.uniprot.org/database/Ensembl> ;
  up:translatedTo <http://rdf.ebi.ac.uk/resource/ensembl.protein/ENSP00000481078.1> ;
  up:transcribedFrom <http://rdf.ebi.ac.uk/resource/ensembl/ENSG00000197978.10> .
<http://rdf.ebi.ac.uk/resource/ensembl.transcript/ENST00000620574.2>
  rdf:type up:Transcript_Resource ;
  up:database <http://purl.uniprot.org/database/Ensembl> ;
  up:translatedTo <http://rdf.ebi.ac.uk/resource/ensembl.protein/ENSP00000479589.1> ;
  up:transcribedFrom <http://rdf.ebi.ac.uk/resource/ensembl/ENSG00000274320.2> .

Changes to the controlled vocabulary of human diseases

New diseases:

• Acromesomelic dysplasia 4
• Anemia, sideroblastic, 5
• B-cell immunodeficiency, distal limb anomalies, and urogenital malformations
• Bardet-Biedl syndrome 20
• Bile acid malabsorption, primary, 2
• Biliary, renal, neurologic, and skeletal syndrome
• Boudin-Mortier syndrome
• Cardiomyopathy, dilated 2E
• Cataract 49
• Central hypoventilation syndrome, congenital, 2, and autonomic dysfunction
• Central hypoventilation syndrome, congenital, 3
• Cerebellar ataxia, brain abnormalities, and cardiac conduction defects
• Cerebral cavernous malformations 4
• Charcot-Marie-Tooth disease 2FF
• Charcot-Marie-Tooth disease 2HH
• Cholestasis, progressive familial intrahepatic, 6
• Cholestasis, progressive familial intrahepatic, 7, with or without hearing loss
• Cholestasis, progressive familial intrahepatic, 8
• Chopra-Amiel-Gordon syndrome
• Ciliary dyskinesia, primary, 47, and lissencephaly
• Cone-rod dystrophy 22
• Congenital disorder of glycosylation 2V
• Congenital disorder of glycosylation 2W
• Congenital heart defects, multiple types, 8, with or without heterotaxy
• Deafness, autosomal dominant, 81
• Deafness, autosomal recessive, 118, with cochlear aplasia
• Deafness, autosomal recessive, 119
• DEGCAGS syndrome
• Delayed puberty, self-limited
• Developmental and epileptic encephalopathy 97
• Developmental and epileptic encephalopathy 98
• Developmental and epileptic encephalopathy 99
• Developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities
• Developmental delay, impaired speech, and behavioral abnormalities
• Developmental delay with or without intellectual impairment or behavioral abnormalities
• Dyskinesia with orofacial involvement, autosomal recessive
• Dystonia 31
• Dystonia 32
• Epidermolysis bullosa simplex 2A, generalized severe
• Epidermolysis bullosa simplex 2B, generalized intermediate
• Epidermolysis bullosa simplex 2C, localized
• Epidermolysis bullosa simplex 2D, generalized, intermediate or severe, autosomal recessive
• Epilepsy, idiopathic generalized 17
• Epilepsy, idiopathic generalized 18
• Facioscapulohumeral muscular dystrophy 3, digenic
• Facioscapulohumeral muscular dystrophy 4, digenic
• Febrile seizures, familial, 2
• Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies
• Hardikar syndrome
• Hengel-Maroofian-Schols syndrome
• Heterotaxy, visceral, 10, autosomal, with male infertility
• Heterotaxy, visceral, 11, autosomal, with male infertility
• Heterotaxy, visceral, 12, autosomal
• Hypoplastic femurs and pelvis
• Immunodeficiency 85
• Immunodeficiency 86
• Immunodeficiency 87 and autoimmunity
• Immunodeficiency 88
• Immunodeficiency 89 and autoimmunity
• Immunodeficiency 91 and hyperinflammation
• Immunodeficiency 92
• Intellectual developmental disorder, X-linked, syndromic, with pigmentary mosaicism and coarse facies
• Intellectual developmental disorder with hypotonia, impaired speech, and dysmorphic facies
• Interstitial lung disease 1
• Joubert syndrome 38
• Joubert syndrome 39
• Joubert syndrome 40
• King-Denborough syndrome
• Loeys-Dietz syndrome 6
• Marbach-Schaaf neurodevelopmental syndrome
• Muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndrome
• Muscular dystrophy, limb-girdle, autosomal recessive 27
• Nephronophthisis-like nephropathy 2
• Neurodevelopmental-craniofacial syndrome with variable renal and cardiac abnormalities
• Neurodevelopmental disorder, non-progressive, with spasticity and transient opisthotonus
• Neurodevelopmental disorder with dysmorphic facies and thin corpus callosum
• Neurodevelopmental disorder with hearing loss and spasticity
• Neurodevelopmental disorder with hyperkinetic movements and dyskinesia
• Neurodevelopmental disorder with hypotonia and brain abnormalities
• Neurodevelopmental disorder with hypotonia and dysmorphic facies
• Neurodevelopmental disorder with hypotonia and gross motor and speech delay
• Neurodevelopmental disorder with impaired language and ataxia and with or without seizures
• Neurodevelopmental disorder with motor and speech delay and behavioral abnormalities
• Neurodevelopmental disorder with seizures and brain abnormalities
• Neuroocular syndrome
• Oculopharyngodistal myopathy 3
• Oocyte maturation defect 11
• Osteosclerotic metaphyseal dysplasia
• Ovarian dysgenesis 9
• Parkinson disease 24, autosomal dominant
• Pontocerebellar hypoplasia 16
• Retinitis pigmentosa 91
• Retinitis pigmentosa 92
• Rhizomelic dysplasia, Ain-Naz type
• Sd(a) polyagglutination syndrome
• Short-rib thoracic dysplasia 21 without polydactyly
• Short stature, Dauber-Argente type
• Short stature, impaired intellectual development, microcephaly, hypotonia, and ocular anomalies
• Spastic paraplegia 84, autosomal recessive
• Spermatogenic failure 56
• Spermatogenic failure 57
• Spermatogenic failure 58
• Spermatogenic failure 59
• Spermatogenic failure 60
• Spermatogenic failure 61
• Spermatogenic failure 62
• Spermatogenic failure 63
• Spondylometaphyseal dysplasia, Pagnamenta type
• Usmani-Riazuddin syndrome, autosomal dominant
• Usmani-Riazuddin syndrome, autosomal recessive
• Ventriculomegaly and arthrogryposis
• VISS syndrome
• Zaki syndrome

Modified diseases:

• Acromesomelic chondrodysplasia, Grebe type -> Acromesomelic dysplasia 2A
• Acromesomelic chondrodysplasia, Hunter-Thompson type -> Acromesomelic dysplasia 2C
• Acromesomelic dysplasia, Demirhan type -> Acromesomelic dysplasia 3
• Acromesomelic dysplasia, Maroteaux type -> Acromesomelic dysplasia 1
• Alopecia-mental retardation syndrome 4 -> Alopecia-intellectual disability syndrome 4
• Ataxia with isolated vitamin E deficiency -> Ataxia with vitamin E deficiency
• Bardet-Biedl syndrome 20 -> Bardet-Biedl syndrome 22
• Du Pan syndrome -> Acromesomelic dysplasia 2B
• Hypogonadotropic hypogonadism 23 without anosmia -> Hypogonadotropic hypogonadism 23 with or without anosmia
• Hypogonadotropic hypogonadism 24 without anosmia -> Hypogonadotropic hypogonadism 24 with or without anosmia
• Immunodeficiency 60 -> Immunodeficiency 60 and autoimmunity
• Mental retardation, autosomal dominant 39 -> Intellectual developmental disorder, autosomal dominant 39
• Mental retardation, autosomal dominant 42 -> Intellectual developmental disorder, autosomal dominant 42
• Mental retardation, autosomal dominant 55, with seizures -> Intellectual developmental disorder, autosomal dominant 55, with seizures
• Mental retardation, autosomal dominant 56 -> Intellectual developmental disorder, autosomal dominant 56
• Mental retardation, autosomal recessive 6 -> Intellectual developmental disorder, autosomal recessive 6
• Mental retardation, autosomal recessive 18 -> Intellectual developmental disorder, autosomal recessive 18, with or without epilepsy
• Mental retardation, autosomal recessive 27 -> Intellectual developmental disorder, autosomal recessive 27
• Mental retardation, autosomal recessive 39 -> Intellectual developmental disorder, autosomal recessive 39
• Mental retardation, autosomal recessive 43 -> Intellectual developmental disorder, autosomal recessive 43
• Mental retardation, autosomal recessive 53 -> Intellectual developmental disorder, autosomal recessive 53
• Mental retardation, autosomal recessive 57 -> Intellectual developmental disorder, autosomal recessive 57
• Mental retardation, autosomal recessive 58 -> Intellectual developmental disorder, autosomal recessive 58
• Myasthenic syndrome, congenital, 7, presynaptic -> Myasthenic syndrome, congenital, 7A, presynaptic, and distal motor neuropathy, autosomal dominant
• Pulmonary fibrosis, idiopathic -> Interstitial lung disease 2
• Rolandic epilepsy with speech dyspraxia and mental retardation X-linked -> Rolandic epilepsy, impaired intellectual development, and speech dyspraxia, X-linked
• Spastic paraplegia 35, autosomal recessive -> Spastic paraplegia 35, autosomal recessive, with or without neurodegeneration
• Ventricular arrythmias due to cardiac ryanodine receptor calcium release deficiency syndrome -> Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome

Changes to the controlled vocabulary for PTMs

New term for the feature key 'Cross-link' ('CROSSLNK' in the flat file):

• 2-(cystein-S-ylcarbonyl)-3-methyl-4-(glutam-5-yloxy)methylindole (Glu-Cys)

New term for the feature key 'Lipidation' ('LIPID' in the flat file):

• N6-stearoyl lysine

Changes in subcellular location controlled vocabulary

New subcellular location:

• Encapsulin nanocompartment

Changes to keywords

New keyword:

• Encapsulin nanocompartment

UniParc news

Version numbers for identifiers in Ensembl cross-references

In UniParc cross-references to Ensembl, we are now using version numbers for Ensembl identifiers wherever possible.

XML format

Example: UPI000442D01A

Previous format:

<dbReference type="Ensembl" id="ENSP00000481078" version_i="1" active="Y" created="2014-07-21" last="2021-10-18">
  <property type="NCBI_taxonomy_id" value="9606"/>
  <property type="gene_name" value="GOLGA6L9"/>
  <property type="proteome_id" value="UP000005640"/>
  <property type="component" value="Chromosome 15"/>
</dbReference>

New format:

<dbReference type="Ensembl" id="ENSP00000481078" version_i="1" active="Y" version="1" created="2014-07-21" last="2021-10-18">
  <property type="NCBI_taxonomy_id" value="9606"/>
  <property type="gene_name" value="GOLGA6L9"/>
  <property type="proteome_id" value="UP000005640"/>
  <property type="component" value="Chromosome 15"/>
</dbReference>

RDF format

Example: UPI000442D01A

Previous format:

uniparc:UPI000442D01A
  rdf:type up:Sequence ;
  up:sequenceFor uniprot:A6NEM1 , isoform:A6NEM1-1 , ensembl:ENSP00000481078 .

ensembl:ENSP00000481078
  up:database <http://purl.uniprot.org/database/Ensembl> ;
  up:version 1 .

New format:

uniparc:UPI000442D01A
  rdf:type up:Sequence ;
  up:sequenceFor uniprot:A6NEM1 , isoform:A6NEM1-1 , ensembl:ENSP00000481078.1 .

ensembl:ENSP00000481078.1
  up:database <http://purl.uniprot.org/database/Ensembl> ;
  up:version 1 ;
  up:reportedVersion 1 .

Headline

A phospholipase for clear vision

The eye is a fascinating and complex organ, made of three main tissue types, the cornea, lens and retina. The eye lens is a transparent and biconvex structure which allows the passage of light, focusing it on the retina. To achieve their specific refractive properties, lens cells differentiate to contain an extraordinarily high concentration of crystallin proteins. They also have to get rid of organelles, such as endoplasmic reticulum, lysosomes and highly diffracting nuclei and mitochondria, to ensure clear vision. This process is under tight spatiotemporal control, proceeding from the center of the lens to the periphery to form an organelle-free zone. Failure of this process leads to a cloudy lens, in other words a cataract.

Some components in the eye lens differentiation process have been identified. The transcription factor HSF4 has been previously shown to be instrumental, although its precise action is unclear. It has also been shown that the degradation of nuclear DNA requires lysosomal DNASE2B. But until recently the process of organelle clearance remained quite elusive. Macroautophagy seemed to be a sensible hypothesis, as it is involved in organelle clearance during red blood cell differentiation for instance. However, this hypothesis has been discarded, as knockout mice lacking Atg5 or Pik3c3, two genes required for autophagy, exhibit normal organelle degradation during lens development.

Recently, Morishita et al. achieved a real breakthrough with a very efficient, though cumbersome approach. Using zebrafish as an animal model, they knocked out, one by one, all the genes that are highly expressed in the lens. In the plaat1 knockout, the disappearance of mitochondria and the endoplasmic reticulum in the lens was almost completely suppressed. The knockout of the orthologous gene in mouse, called Plaat3, gave a similar result: there was almost no degradation of mitochondria, endoplasmic reticulum or lysosomes in the developing lens. PLAAT proteins are phospholipases, that exhibit both phospholipase A1 (PLA1) and A2 (PLA2) activities, and hence they catalyze the calcium-independent release of fatty acids from the sn-1 or sn-2 position of glycerophospholipids. In the context of lens, the lipase activity was required for rupture of organelles. During lens differentiation, PLAAT cytosolic enzymes are recruited to the organelles to be degraded after a mysterious membrane-damaging event. The cause of the membrane damage that initiates PLAAT recruitment and the cascade of organelle membrane degradation is unknown, but it is dependent upon HSF4 expression. One hypothesis is that high levels of expression of cytosolic proteins induced by HSF4, such as crystallins, may cause the membrane damage. What is the fate of the proteins released during organelle degradation? Are they degraded through the ubiquitin-proteasome pathway? What happens to the free fatty acids that are generated by PLAAT activity? These questions and many others remain open, but some (refracted) light has been shed on an until recently obscure process.

UniProtKB/Swiss-Prot entries for plaat1, PLAAT3 and HSF4 have been updated with new information.

UniProtKB news

Cross-references to MANE-Select

Cross-references have been added to the MANE-Select (Matched Annotation between NCBI and EBI) transcript resource. Matched Annotation from NCBI and EMBL-EBI (MANE) is a collaboration between the NCBI and the EMBL-EBI with the goal to provide a minimal set of matching RefSeq and Ensembl transcripts of human protein-coding genes.

MANE Select aims at providing one high-quality representative transcript per protein-coding gene that is well-supported by experimental data and represents the biology of the gene.

MANE-Select is available at https://www.ensembl.org/info/genome/genebuild/mane.html and https://www.ncbi.nlm.nih.gov/refseq/MANE/.

The format of the explicit links is:

Resource abbreviation	MANE-Select
Resource identifier	Ensembl transcript sequence ID
Optional information 1	Ensembl protein sequence ID
Optional information 2	RefSeq nucleotide sequence ID
Optional information 3	RefSeq protein sequence ID

Example: Q9Y4I1

Show all entries having a cross-reference to MANE-Select.

Cross-references to MANE-Select may be isoform-specific. The general format of isoform-specific cross-references was described in release 2014_03.

Text format

Example: Q9Y4I1

DR   MANE-Select; ENST00000399233.7; ENSP00000382179.4; NM_001382347.1; NP_001369276.1. [Q9Y4I1-3]

XML format

Example: Q9Y4I1

<dbReference type="MANE-Select" id="ENST00000399233.7">
  <property type="protein sequence ID" value="ENSP00000382179.4"/>
  <property type="RefSeq nucleotide sequence ID" value="NM_001382347.1"/>
  <property type="RefSeq protein sequence ID" value="NP_001369276.1"/>
  <molecule id="Q9Y4I1-3"/>
</dbReference>

RDF format

Example: Q9Y4I1

uniprot:Q9Y4I1
  rdfs:seeAlso <http://purl.uniprot.org/mane-select/ENST00000399233.7> .

<http://purl.uniprot.org/mane-select/ENST00000399233.7>
  rdf:type up:Transcript_Resource ;
  up:database <http://purl.uniprot.org/database/MANE-Select> ;
  owl:sameAs <http://rdf.ebi.ac.uk/resource/ensembl.transcript/ENST00000399233.7> ;
  owl:sameAs <http://purl.uniprot.org/refseq/NM_001382347.1> ;
  uniprot:translatedTo <http://purl.uniprot.org/mane-select/ENST00000399233.7#translation> ;
  rdfs:seeAlso isoform:Q9Y4I1-3 .

<http://purl.uniprot.org/mane-select/ENST00000399233.7#translation>
  owl:sameAs <http://rdf.ebi.ac.uk/resource/ensembl.protein/ENSP00000382179.4> ;
  owl:sameAs <http://purl.uniprot.org/refseq/NP_001369276.1> .

Removal of the cross-references to GeneDB

Cross-references to GeneDB have been removed.

Change of ECO code associated with the GOA evidence 'Inferred from Electronic Annotation' (IEA)

Following a decision of the Gene Ontology (GO), we now associate, in Gene Ontology annotations, the evidence type 'Inferred from Electronic Annotation' (IEA) with the Evidence Ontology (ECO) term

'computational evidence used in automatic assertion', identified with ECO:0007669

replacing the previously used

'evidence used in automatic assertion', identified with ECO:0000501.

This affects the RDF formats of UniProtKB/GOA data.

Changes to the controlled vocabulary of human diseases

New diseases:

• Aicardi-Goutieres syndrome 8
• Anencephaly 2
• Angioedema, hereditary, 4
• Angioedema, hereditary, 5
• Angioedema, hereditary, 6
• Angioedema, hereditary, 7
• Angioedema, hereditary, 8
• Ataxia, intention tremor, and hypotonia syndrome, childhood-onset
• Autoinflammatory syndrome, familial, with or without immunodeficiency
• Cardiomyopathy, dilated 2D
• Cardiomyopathy, familial hypertrophic 28
• Cardiomyopathy, familial restrictive 6
• Ciliary dyskinesia, primary, 46
• Combined oxidative phosphorylation deficiency 52
• Combined oxidative phosphorylation deficiency 53
• Cutis laxa, autosomal recessive, 2E
• Deafness, cataract, impaired intellectual development, and polyneuropathy
• Diarrhea 12, with microvillus atrophy
• Encephalitis, acute, infection (viral)-induced, 11
• Faundes-Banka syndrome
• Focal segmental glomerulosclerosis and neurodevelopmental syndrome
• Galloway-Mowat syndrome 9
• Galloway-Mowat syndrome 10
• Hemolytic disease of fetus and newborn, RH-induced
• Hypertriglyceridemia 2
• Hypotaurinemic retinal degeneration and cardiomyopathy
• Hypertrophic osteoarthropathy, primary, autosomal dominant
• Hypokalemic tubulopathy and deafness
• Immunodeficiency 81
• Immunodeficiency 82 with systemic inflammation
• Immunodeficiency 84
• Inflammatory bowel disease 31, autosomal recessive
• Leber hereditary optic neuropathy, autosomal recessive
• Luo-Schoch-Yamamoto syndrome
• Lymphatic malformation 10
• Lymphatic malformation 11
• Martsolf syndrome 2
• Megacystis-microcolon-intestinal hypoperistalsis syndrome 3
• Megacystis-microcolon-intestinal hypoperistalsis syndrome 4
• Megacystis-microcolon-intestinal hypoperistalsis syndrome 5
• Microcephaly 28, primary, autosomal recessive
• Mitochondrial complex IV deficiency, nuclear type 22
• Mitochondrial DNA depletion syndrome 16B, neuroophthalmic type
• Myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive
• Myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy
• Neurodevelopmental disorder with hypotonia, facial dysmorphism, and brain abnormalities
• Neurodevelopmental disorder with infantile epileptic spasms
• Neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 2
• Onychodystrophy, osteodystrophy, impaired intellectual development, and seizures syndrome
• Osteootohepatoenteric syndrome
• Portal hypertension, non-cirrhotic, 2
• Retinal dystrophy and microvillus inclusion disease
• Ritscher-Schinzel syndrome 4
• Sick sinus syndrome 4
• Spermatogenic failure 54
• Spermatogenic failure 55
• Spinocerebellar ataxia, autosomal recessive, 29
• Spinocerebellar ataxia, autosomal recessive, 30
• Spinocerebellar ataxia, autosomal recessive, 31
• Ventricular arrythmias due to cardiac ryanodine receptor calcium release deficiency syndrome
• Visceral neuropathy, familial, 1, autosomal recessive
• Visceral neuropathy, familial, 2, autosomal recessive
• WHIM syndrome 2
• White-Kernohan syndrome

Modified diseases:

• 2-aminoadipic 2-oxoadipic aciduria -> Alpha-aminoadipic and alpha-ketoadipic aciduria
• Activated PI3K-delta syndrome -> Immunodeficiency 14A, autosomal dominant
• AICAR transformylase/IMP cyclohydrolase deficiency -> AICA-ribosuria due to ATIC deficiency
• Anencephaly -> Anencephaly 1
• Arthrogryposis multiplex congenita, myogenic type -> Arthrogryposis multiplex congenita 3, myogenic type
• Arthrogryposis multiplex congenita, neurogenic, with myelin defect -> Arthrogryposis multiplex congenita 1, neurogenic, with myelin defect
• Arthrogryposis multiplex congenita, neurogenic type -> Arthrogryposis multiplex congenita 2, neurogenic type
• Ceroid lipofuscinosis, neuronal, 4A -> Ceroid lipofuscinosis, neuronal, 4A (Kufs type), autosomal recessive
• Ceroid lipofuscinosis, neuronal, 4B -> Ceroid lipofuscinosis, neuronal, 4B (Kufs type), autosomal dominant
• Ceroid lipofuscinosis, neuronal, 13 -> Ceroid lipofuscinosis, neuronal, 13 (Kufs type)
• Eiken skeletal dysplasia -> Eiken syndrome
• Encephalopathy, acute, infection-induced, Herpes-specific, 1 -> Encephalopathy, acute, infection-induced, 1, herpes-specific
• Encephalopathy, acute, infection-induced, Herpes-specific, 2 -> Immunodeficiency 83, susceptibility to viral infections
• Encephalopathy, acute, infection-induced, Herpes-specific, 5 -> Encephalopathy, acute, infection-induced, 5, herpes-specific
• Encephalopathy, acute, infection-induced, Herpes-specific, 6 -> Encephalopathy, acute, infection-induced, 6, herpes-specific
• Encephalopathy, acute, infection-induced, Herpes-specific, 7 -> Encephalopathy, acute, infection-induced, 7, herpes-specific
• Encephalopathy, acute, infection-induced, herpes-specific, 8 -> Encephalopathy, acute, infection-induced, 8, herpes-specific
• Epilepsy, focal, with speech disorder and with or without mental retardation -> Epilepsy, focal, with speech disorder and with or without impaired intellectual development
• Epilepsy X-linked, with variable learning disabilities and behavior disorders -> Epilepsy, X-linked, with variable learning disabilities and behavior disorders
• Epileptic encephalopathy, childhood-onset -> Develomental and epileptic encephalopathy 94
• Epileptic encephalopathy, early infantile, 77 -> Multiple congenital anomalies-hypotonia-seizures syndrome 4
• Familial hypercholanemia -> Hypercholanemia, familial, 1
• Familial juvenile hyperuricemic nephropathy 1 -> Tubulointerstitial kidney disease, autosomal dominant, 1
• Familial juvenile hyperuricemic nephropathy 2 -> Tubulointerstitial kidney disease, autosomal dominant, 4
• Familial juvenile hyperuricemic nephropathy 4 -> Tubulointerstitial kidney disease, autosomal dominant, 5
• Facioscapulohumeral muscular dystrophy 2 -> Facioscapulohumeral muscular dystrophy 2, digenic
• Glanzmann thrombasthenia -> Glanzmann thrombasthenia 1
• Gout HPRT-related -> Hyperuricemia, HPRT-related
• Granulomatous disease, chronic, cytochrome-b-negative, autosomal recessive -> Granulomatous disease, chronic, autosomal recessive, 4
• Granulomatous disease, chronic, cytochrome-b-positive 1, autosomal recessive -> Granulomatous disease, chronic, autosomal recessive, 1
• Granulomatous disease, chronic, cytochrome-b-positive 2, autosomal recessive -> Granulomatous disease, chronic, autosomal recessive, 2
• Granulomatous disease, chronic, cytochrome-b-positive 3, autosomal recessive -> Granulomatous disease, chronic, autosomal recessive, 3
• Growth hormone insensitivity with immunodeficiency -> Growth hormone insensitivity syndrome with immune dysregulation 1, autosomal recessive
• Hemophagocytic lymphohistiocytosis, familial, 5 -> Hemophagocytic lymphohistiocytosis, familial, 5, with or without microvillus inclusion disease
• Hereditary angioedema -> Angioedema, hereditary
• Hereditary angioedema 3 -> Angioedema, hereditary, 3
• Hypertelorism, Teebi type -> Teebi hypertelorism syndrome
• Hypophosphatasia childhood type -> Hypophosphatasia, childhood
• Hypophosphatasia infantile type -> Hypophosphatasia, infantile
• IFAP syndrome with or without BRESHECK syndrome -> IFAP syndrome 1, with or without Bresheck syndrome
• Immunodeficiency, common variable, 12 -> Immunodeficiency, common variable, 12, with autoimmunity
• Inflammatory bowel disease 25 -> Inflammatory bowel disease 25, autosomal recessive
• Inflammatory bowel disease 28 -> Inflammatory bowel disease 28, autosomal recessive
• Isolated congenital nail clubbing -> Digital clubbing, isolated congenital
• Leber hereditary optic neuropathy modifier -> Leber hereditary optic neuropathy, modifier
• Martsolf syndrome -> Martsolf syndrome 1
• Medullary cystic kidney disease 1 -> Tubulointerstitial kidney disease, autosomal dominant, 2
• Mental retardation, autosomal dominant 11 -> Intellectual developmental disorder, autosomal dominant 11
• Mental retardation, autosomal dominant 18 -> Gand syndrome
• Mental retardation, autosomal dominant 31 -> Neurodevelopmental disorder with neonatal respiratory insufficiency, hypotonia, and feeding difficulties
• Mental retardation, autosomal dominant 50 -> Intellectual developmental disorder, autosomal dominant 50, with behavioral abnormalities
• Mental retardation, autosomal recessive 12 -> Intellectual developmental disorder, autosomal recessive 12
• Mental retardation, autosomal recessive 49 -> Neurodevelopmental disorder with spastic paraplegia and microcephaly
• Mental retardation, autosomal recessive 55 -> Neurodevelopmental disorder with microcephaly and gray sclerae
• Mental retardation, X-linked, associated with fragile site FRAXE -> Intellectual developmental disorder, X-linked 109
• Mental retardation, X-linked, syndromic, 11 -> Intellectual developmental disorder, X-linked, syndromic 11
• Mental retardation, X-linked, syndromic, 13 -> Intellectual developmental disorder, X-linked, syndromic 13
• Mental retardation, X-linked, syndromic, 14 -> Intellectual developmental disorder, X-linked, syndromic 14
• Mental retardation, X-linked, syndromic, 15 -> Intellectual developmental disorder, X-linked, syndromic, Cabezas type
• Mental retardation, X-linked, syndromic, 28 -> Intellectual developmental disorder, X-linked, syndromic 28
• Mental retardation, X-linked, syndromic, 32 -> Intellectual developmental disorder, X-linked, syndromic 32
• Mental retardation, X-linked, syndromic, 33 -> Intellectual developmental disorder, X-linked, syndromic 33
• Mental retardation, X-linked, syndromic, 34 -> Intellectual developmental disorder, X-linked, syndromic 34
• Mental retardation, X-linked, syndromic, 35 -> Intellectual developmental disorder, X-linked, syndromic 35
• Mental retardation, X-linked, syndromic, Bain type -> Intellectual developmental disorder, X-linked, syndromic, Bain type
• Mental retardation, X-linked, syndromic, Claes-Jensen type -> Intellectual developmental disorder, X-linked, syndromic, Claes-Jensen type
• Mental retardation, X-linked, syndromic, Christianson type -> Intellectual developmental disorder, X-linked, syndromic, Christianson type
• Mental retardation, X-linked, syndromic, Houge type -> Intellectual developmental disorder, X-linked, syndromic, Houge type
• Mental retardation, X-linked, syndromic, Lubs type -> Intellectual developmental disorder, X-linked, syndromic, Lubs type
• Mental retardation, X-linked, syndromic, Nascimento-type -> Intellectual developmental disorder, X-linked, syndromic, Nascimento-type
• Mental retardation, X-linked, syndromic, OPHN1-related -> Intellectual developmental disorder, X-linked, syndromic, Billuart type
• Mental retardation, X-linked, syndromic, Siderius type -> Intellectual developmental disorder, X-linked, syndromic, Siderius type
• Mental retardation, X-linked, syndromic, Stocco dos Santos type -> Intellectual developmental disorder, X-linked, syndromic, Stocco dos Santos type
• Mental retardation, X-linked, syndromic, Turner type -> Intellectual developmental disorder, X-linked, syndromic, Turner type
• Mental retardation, X-linked, with epilepsy -> Intellectual developmental disorder, X-linked, syndromic, Hedera type
• Mental retardation, X-linked, with isolated growth hormone deficiency -> Intellectual developmental disorder, X-linked, with isolated growth hormone deficiency
• Mental retardation, X-linked, with or without seizures, ARX-related -> Intellectual developmental disorder, X-linked 29
• Mental retardation, X-linked 1 -> Intellectual developmental disorder, X-linked 1
• Mental retardation, X-linked 12 -> Intellectual developmental disorder, X-linked 12
• Mental retardation, X-linked 19 -> Intellectual developmental disorder, X-linked 19
• Mental retardation, X-linked 21 -> Intellectual developmental disorder, X-linked 21
• Mental retardation, X-linked 30 -> Intellectual developmental disorder, X-linked 30
• Mental retardation, X-linked 41 -> Intellectual developmental disorder, X-linked 41
• Mental retardation, X-linked 44 -> Intellectual developmental disorder, X-linked 9
• Mental retardation, X-linked 50 -> Intellectual developmental disorder, X-linked 50
• Mental retardation, X-linked 58 -> Intellectual developmental disorder, X-linked 58
• Mental retardation, X-linked 63 -> Intellectual developmental disorder, X-linked 63
• Mental retardation, X-linked 72 -> Intellectual developmental disorder, X-linked 72
• Mental retardation, X-linked 90 -> Intellectual developmental disorder, X-linked 90
• Mental retardation, X-linked 93 -> Intellectual developmental disorder, X-linked 93
• Mental retardation, X-linked 94 -> Intellectual developmental disorder, X-linked, syndromic, Wu type
• Mental retardation, X-linked 96 -> Intellectual developmental disorder, X-linked 96
• Mental retardation, X-linked 97 -> Intellectual developmental disorder, X-linked 97
• Mental retardation, X-linked 98 -> Intellectual developmental disorder, X-linked 98
• Mental retardation, X-linked 99 -> Intellectual developmental disorder, X-linked 99
• Mental retardation, X-linked 99, syndromic, female-restricted -> Intellectual developmental disorder, X-linked 99, syndromic, female-restricted
• Mental retardation, X-linked 100 -> Intellectual developmental disorder, X-linked 100
• Mental retardation, X-linked 101 -> Intellectual developmental disorder, X-linked 101
• Mental retardation, X-linked 103 -> Intellectual developmental disorder, X-linked 103
• Mental retardation, X-linked 104 -> Intellectual developmental disorder, X-linked 104
• Mental retardation, X-linked 105 -> Intellectual developmental disorder, X-linked 105
• Mental retardation, X-linked 106 -> Intellectual developmental disorder, X-linked 106
• Mental retardation, X-linked 107 -> Intellectual developmental disorder, X-linked 107
• Mental retardation and distinctive facial features with or without cardiac defects -> Impaired intellectual development and distinctive facial features with or without cardiac defects
• Mental retardation and microcephaly with pontine and cerebellar hypoplasia -> Intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia
• Methylenetetrahydrofolate reductase deficiency -> Homocystinuria due to deficiency of N(5,10)-methylenetetrahydrofolate reductase activity
• Microcephaly, epilepsy, and diabetes syndrome -> Microcephaly, epilepsy, and diabetes syndrome 1
• Microcephaly 15, primary, autosomal recessive -> Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain imaging abnormalities
• Mismatch repair cancer syndrome -> Mismatch repair cancer syndrome 1
• Muscular dystrophy-dystroglycanopathy congenital with mental retardation B1 -> Muscular dystrophy-dystroglycanopathy congenital with impaired intellectual development B1
• Muscular dystrophy-dystroglycanopathy congenital with mental retardation B2 -> Muscular dystrophy-dystroglycanopathy congenital with impaired intellectual development B2
• Muscular dystrophy-dystroglycanopathy congenital with mental retardation B3 -> Muscular dystrophy-dystroglycanopathy congenital with impaired intellectual development B3
• Muscular dystrophy-dystroglycanopathy congenital without mental retardation B4 -> Muscular dystrophy-dystroglycanopathy congenital without impaired intellectual development B4
• Muscular dystrophy-dystroglycanopathy congenital with mental retardation B6 -> Muscular dystrophy-dystroglycanopathy congenital with impaired intellectual development B6
• Muscular dystrophy-dystroglycanopathy congenital with mental retardation B14 -> Muscular dystrophy-dystroglycanopathy congenital with impaired intellectual development B14
• Muscular dystrophy-dystroglycanopathy congenital with or without mental retardation B5 -> Muscular dystrophy-dystroglycanopathy congenital with or without impaired intellectual development B5
• Neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset -> Neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1
• Oculootoradial syndrome -> IVIC syndrome
• Odontochondrodysplasia -> Odontochondrodysplasia 1
• Ondontochondrodysplasia 2 with hearing loss and diabetes -> Odontochondrodysplasia 2 with hearing loss and diabetes
• Otofaciocervical syndrome 2 -> Otofaciocervical syndrome 2, with T-cell deficiency
• Partial gonadal dysgenesis with minifascicular neuropathy 46,XY -> 46,XY gonadal dysgenesis with minifascicular neuropathy
• Platelet abnormalities with eosinophilia and immune-mediated inflammatory disease -> Immunodeficiency 71 with inflammatory disease and congenital thrombocytopenia
• Progressive pseudorheumatoid arthropathy of childhood -> Progressive pseudorheumatoid dysplasia
• Rajab interstitial lung disease with brain calcifications -> Rajab interstitial lung disease with brain calcifications 1
• Renal tubular acidosis, distal, autosomal dominant -> Renal tubular acidosis, distal, 1
• Renal tubular acidosis, distal, autosomal recessive -> Renal tubular acidosis, distal, 3, with or without sensorineural hearing loss
• Renal tubular acidosis, distal, with hemolytic anemia -> Renal tubular acidosis, distal, 4, with hemolytic anemia
• Renal tubular acidosis, distal, with progressive nerve deafness -> Renal tubular acidosis, distal, 2, with progressive sensorineural hearing loss
• Roberts syndrome -> Roberts-SC phocomelia syndrome
• Spondyloepimetaphyseal dysplasia, MATN3-related -> Spondyloepimetaphyseal dysplasia, Borochowitz-Cormier-Daire type
• Visceral myopathy -> Visceral myopathy 1
• Vitreoretinochoroidopathy, autosomal dominant -> Vitreoretinochoroidopathy
• WHIM syndrome -> WHIM syndrome 1
• Wilson-Turner X-linked mental retardation syndrome -> Intellectual developmental disorder, X-linked, syndromic, Wilson-Turner type
• X-linked syndromic mental retardation Snyder-Robinson type -> Intellectual developmental disorder, X-linked, syndromic, Snyder-Robinson type

Deleted diseases

• Glomerulocystic kidney disease with hyperuricemia and isosthenuria
• Medullary cystic kidney disease 2
• Waardenburg syndrome 2, with ocular albinism, autosomal recessive
• SC phocomelia syndrome

Changes to the controlled vocabulary for PTMs

New term for the feature key 'Cross-link' ('CROSSLNK' in the flat file):

• Cyclopeptide (Ile-Lys)

New terms for the feature key 'Lipidation' ('LIPID' in the flat file):

• O-hexanoyl serine
• 3'-farnesyl-2',N2-cyclotryptophan

New terms for the feature key 'Modified residue' ('MOD_RES' in the flat file):

• ADP-riboxanated arginine
• 3'-bromotyrosine

RDF news

Change of the RDF representation of cross-references to RefSeq

We have modified the RDF description of our cross-references to protein resources in the RefSeq database to provide explicit links to their corresponding RefSeq nucleotide sequences.

Previously, our cross-references showed the identifier of a RefSeq nucleotide sequence through an rdfs:comment property with a string literal value. We have replaced this by a translatedFrom property that links the RefSeq protein to a resource that corresponds to its coding sequence (CDS) and, similarly to the description of EMBL-CDS resources, this CDS links through a locatedOn property to the transcript or genomic sequence that contains it.

Note that the translatedFrom property is not the inverse of the translatedTo property that is used, for instance, in the description of Ensembl cross-references. The latter is used to link mature transcripts (whose sequence includes untranslated regions in addition to the CDS) to proteins.

Example: Q00266

Previous format:

uniprot:Q00266
  rdfs:seeAlso <http://purl.uniprot.org/refseq/NP_000420.1> .

<http://purl.uniprot.org/refseq/NP_000420.1>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/RefSeq> ;
  rdfs:comment "NM_000429.2" .

New format:

uniprot:Q00266
  rdfs:seeAlso <http://purl.uniprot.org/refseq/NP_000420.1> .

<http://purl.uniprot.org/refseq/NP_000420.1>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/RefSeq> ;
  up:translatedFrom <http://purl.uniprot.org/refseq/NM_000429.2#NP_000420.1_CDS> .

<http://purl.uniprot.org/refseq/NM_000429.2#NP_000420.1_CDS>
  up:locatedOn <http://purl.uniprot.org/refseq/NM_000429.2> .

Change of the RDF representation of cross-references of tissues

To be consistent between the RDF representation of tissues with the other controlled vocabularies we provide, the tissues cross-references now use the rdfs:comment predicate instead of the previously used rdfs:label predicate.

Example: TS-0430

Previous format:

<http://purl.uniprot.org/tissues/430>
  rdfs:seeAlso <http://purl.uniprot.org/po/0000262> .
<http://purl.uniprot.org/po/0000262>
  rdfs:label "trichoblast" ;
  up:database <http://purl.uniprot.org/database/PO> .

New format:

<http://purl.uniprot.org/tissues/430>
   rdfs:seeAlso <http://purl.uniprot.org/po/0000262> .
<http://purl.uniprot.org/po/0000262>
   rdfs:comment "trichoblast" ;
   up:database <http://purl.uniprot.org/database/PO> .

Headline

ZTGC: bacteriophages reinvent the DNA alphabet

In 1977, Kirnos et al. isolated a DNA virus acting on blue-green algae, called cyanophage S-2L, from water samples taken in the outskirts of Leningrad (known today as Saint Petersburg). They reported a weird DNA composition for this virus. Instead of the usual adenine (6-aminopurine or A), the bacteriophage contained 2,6-diaminopurine (DAP), also known as 2-aminoadenine, abbreviated Z in recent publications. The presence of the additional amino group in adenine changes several DNA features. The most striking difference is that DAP forms 3 hydrogen bonds when paired with thymine, instead of the usual 2 bonds between adenine and thymine, hence forming a stronger, more stable pair. The presence of DAP confers selective advantages to bacteriophages, such as resistance to most restriction enzymes. Consequently, these viruses can evade the host bacterial defense system based on foreign DNA degradation.

In view of the complete substitution of adenine by DAP, Kirnos et al. proposed that DAP was incorporated into S-2L phage DNA as a ready-made nucleotide, rather than formed at the polynucleotide level as a result of amination of adenine residues within DNA. However, it took almost half a century to unravel the pathway of DAP synthesis and its incorporation into DNA. This pathway intermingles viral and bacterial enzymes in tight collaboration. The first step of DAP synthesis involves the condensation of aspartate with deoxyguanylate to form N6-succino-2-amino-2'-deoxyadenylate (dSMP). The reaction is catalyzed by phage PurZ. dSMP is then converted into 2-amino-2'-deoxyadenosine monophosphate (dZMP) by an enzyme encoded by purB. dZMP is further phosphorylated by guanylate kinase (gmk) and by nucleoside diphosphate kinase (ndk) to produce 2-amino-2'-deoxyadenosine-5'-triphosphate (dZTP). All three enzymes, encoded by the purB, gmk and ndk genes, are provided by the bacterial host. dZTP is incorporated into phage DNA by viral DpoZ polymerase, which shares similarity with the Klenow fragment of Escherichia coli DNA polymerase I. The selective incorporation of dZTP rather than dATP into phage DNA is still a matter of debate. Pezo et al. showed that DpoZ has a strong preference for dZTP over dATP. However, Czernecki and Zhou proposed another mechanism of dATP exclusion, in which another phage enzyme, a dATPase called DatZ, would break up dATP, while preserving dZTP. The removal of dATP (and of its precursor dADP) from the nucleotide pool of the host would prevent the incorporation of adenine into the phage genome.

If cyanophage S-2L looked like a strange outlier 50 years ago, nowadays its amazing DNA composition appears to be more widespread than anticipated. PurZ has been identified in over a hundred bacteriophages, that infect a variety of microorganisms, including cyanobacteria, proteobacteria and actinobacteria, and the presence of Z-genomes have been experimentally proven in several of them. DAP usage to convey genetic information may be ancient. Phylogenic trees of PurZ and DpoZ indicate that DAP may have been used among siphoviruses since the evolutionary divergence of actinobacteria, cyanobacteria, and proteobacteria some 3.5 billion years ago. Moreover DAP, along with other nucleobases, has been found in meteorites, suggesting it could have been available before the advent of life for constructing the first genetic molecules.

As of this release, representative entries for the proteins involved in viral Z-genome manufacturing have been manually annotated and are publicly available. These entries include viral PurZ, DNA polymerase DpoZ and dATPase DatZ and bacterial PurB, Gmk and Ndk. Viral PurZ proteins can also be identified with a newly created HAMAP family profile.

It should be noted that DAP has been first abbreviated 'D', but more recently the abbreviation 'Z' took over and DNA containing this nucleotide was called 'Z-DNA'. This latter nomenclature may be misleading. The term 'Z-DNA' classically refers to a specific left-handed double helical structure in which the helix winds to the left in a zigzag pattern, instead of to the right, like the more common B-DNA form. This type of structure does not contain 2,6-diaminopurine.

UniProtKB news

Changes to the controlled vocabulary of human diseases

New diseases:

• Alzahrani-Kuwahara syndrome
• Arthrogryposis multiplex congenita 6
• Azoospermia, obstructive, with nephrolithiasis
• Baralle-Macken syndrome
• Bartsocas-Papas syndrome 2
• Bile acid conjugation defect 1
• Bleeding disorder, platelet-type, 24
• Blepharophimosis-impaired intellectual development syndrome
• Buratti-Harel syndrome
• Cataracts, spastic paraparesis, and speech delay
• Coffin-Siris syndrome 12
• Dysostosis multiplex, Ain-Naz type
• CIMDAG syndrome
• Deafness, autosomal dominant, 80
• Developmental and epileptic encephalopathy 6B
• Developmental and epileptic encephalopathy 96
• Developmental delay with dysmorphic facies and dental anomalies
• Dystonia 30
• Fibromuscular dysplasia, multifocal
• Glanzmann thrombasthenia 2
• Global developmental delay with speech and behavioral abnormalities
• Growth restriction, hypoplastic kidneys, alopecia, and distinctive facies
• Hiatt-Neu-Cooper neurodevelopmental syndrome
• Hypercholanemia, familial, 2
• Immunodeficiency 14B, autosomal recessive
• Immunodeficiency 77
• Immunodeficiency 78 with autoimmunity and developmental delay
• Immunodeficiency 79
• Immunodeficiency 80 with or without congenital cardiomyopathy
• Intellectual developmental disorder, autosomal dominant 65
• Intellectual developmental disorder and hypogonadotropic hypogonadism
• Juberg-Hayward syndrome
• KINSSHIP syndrome
• Kohlschutter-Tonz syndrome-like
• Leukodystrophy, hypomyelinating, 21
• Leukodystrophy, hypomyelinating, 22
• Lymphatic malformation 9
• Mahvash disease
• Marbach-Rustad progeroid syndrome
• Megacystis-microcolon-intestinal hypoperistalsis syndrome 2
• Megaloblastic anemia, folate-responsive
• Microcephaly, epilepsy, and diabetes syndrome 2
• Mitochondrial complex I deficiency, nuclear type 37
• Nephrotic syndrome 24
• Neurodegeneration with ataxia and late-onset optic atrophy
• Neurodevelopmental disorder with cerebral atrophy and variable facial dysmorphism
• Neurodevelopmental disorder with cerebellar atrophy and motor dysfunction
• Neurodevelopmental disorder with dysmorphic facies and cerebellar hypoplasia
• Neurodevelopmental disorder with dysmorphic facies and variable seizures
• Neurodevelopmental disorder with or without autism or seizures
• Neurodevelopmental disorder with seizures and gingival overgrowth
• Neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasia
• Oculogastrointestinal neurodevelopmental syndrome
• Ondontochondrodysplasia 2 with hearing loss and diabetes
• Parkinsonism with polyneuropathy
• Pontocerebellar hypoplasia 14
• Pontocerebellar hypoplasia 15
• Pontocerebellar hypoplasia 1E
• Pontocerebellar hypoplasia 1F
• Premature ovarian failure 19
• Radio-Tartaglia syndrome
• Roifman-Chitayat syndrome
• Short stature, oligodontia, dysmorphic facies, and motor delay
• Spermatogenic failure 53
• Spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and Leber congenital amaurosis
• Visceral myopathy 2
• Vitreoretinopathy with phalangeal epiphyseal dysplasia

Modified diseases:

• Bleeding disorder, platelet-type 8 -> Bleeding disorder, platelet-type, 8
• Bleeding disorder, platelet-type 11 -> Bleeding disorder, platelet-type, 11
• Bleeding disorder, platelet-type 13 -> Bleeding disorder, platelet-type, 13
• Bleeding disorder, platelet-type 16 -> Bleeding disorder, platelet-type, 16
• Bleeding disorder, platelet-type 15 -> Bleeding disorder, platelet-type, 15
• Bleeding disorder, platelet-type 17 -> Bleeding disorder, platelet-type, 17
• Bleeding disorder, platelet-type 18 -> Bleeding disorder, platelet-type, 18
• Bleeding disorder, platelet-type 19 -> Bleeding disorder, platelet-type, 19
• Bleeding disorder, platelet-type 20 -> Bleeding disorder, platelet-type, 20
• Bleeding disorder, platelet-type 21 -> Bleeding disorder, platelet-type, 21
• Bleeding disorder, platelet-type 22 -> Bleeding disorder, platelet-type, 22

Changes to the controlled vocabulary for PTMs

New term for the feature key 'Cross-link' ('CROSSLNK' in the flat file):

• 4-(1-hydroxyethyl)-7-isoleucino-2-(threonin-O3-ylcarbonyl)-7,8-dihydroquinolin-8-ol (Ile-Thr)

New term for the feature key 'Lipidation' ('LIPID' in the flat file):

• Phosphatidylserine amidated glycine

New terms for the feature key 'Modified residue' ('MOD_RES' in the flat file):

• 5-glutamyl glycine
• ADP-alpha-D-ribosylarginine

Headline

The importance of being disordered

Intrinsically disordered regions are protein regions that lack a fixed or ordered three-dimensional structure, typically in the absence of interaction partners. They are thought to often drive liquid-liquid phase separation within cells. This process leads to the formation of biomolecular condensates devoid of a surrounding lipid membrane, which are responsible for extensively compartmentalizing eukaryotic cells. Liquid-liquid phase separation plays crucial roles in fundamental cellular processes, such as the stress response, among others. Indeed eukaryotic cells react to a wide range of stresses by assembling proteins and mRNAs into massive ribonucleoprotein stress granules (SGs) that regulate mRNA translation and degradation. Interestingly mRNAs modified through the methylation of adenosine (m⁶A) are enriched in SGs. The m⁶A modification is very common, with around 25% of mRNAs containing at least one m⁶A. It is recognized by a protein domain, called YTH, which is conserved from yeast to humans. In humans and mice, there are 3 such proteins, YTHDF1, YTHDF2 and YTHDF3. All 3 paralogs contain a C-terminal YTH domain and disordered regions are predicted in their N-terminal moieties. These proteins colocalize with stress granules.

Could YTHDF proteins and their modified RNA partners be active players in the process of stress granule formation? In vitro, RNAs containing at least 4 copies of m⁶A motifs, but not those with a single motif, dramatically enhance phase separation of YTHDF proteins. When transfected into cells, multivalent m⁶A RNA oligos promote localization of YTHDF proteins to stress granules. Moreover, depletion of YTHDF proteins inhibits SG formation and recruitment of mRNAs to SGs. Both the N-terminal intrinsically disordered region and the C-terminal m⁶A-binding YTH domain of YTHDF proteins are required for SG formation. It has been proposed that polymethylated mRNAs may act as a multivalent scaffold for the binding of YTHDF proteins, juxtaposing their low-complexity domains and thereby leading to phase separation.

As of this release, we have introduced predictions of long, intrinsically disordered regions into the UniProtKB annotation pipeline, using the MobiDB-lite method. YTHDF entries have been updated and are now publicly available.

UniProt knowledge graph news

Using UniProt in a public cloud is now easier than ever, as UniProt is now available as part of the AWS open data program. AWS has published a "tutorial on how you can use the public UniProt data in
your own private graph database":https://aws.amazon.com/blogs/industries/exploring-the-uniprot-protein-knowledgebase-with-aws-open-data-and-amazon-neptune/ using AWS Neptune. This shows how the I (for Interoperability) in FAIR UniProt works with commercial cloud-based tools. Of course the UniProt Knowledge Graph remains freely available at sparql.uniprot.org.

UniProtKB news

Introduction of MobiDB-lite predictions for intrinsically disordered regions

Starting with this release of UniProt, we import predictions of intrinsically disordered regions and regions of compositional bias, generated with the MobiDB-lite method, in UniProtKB/Swiss-Prot. These computationally generated annotations are represented as Region and Compositional bias annotations tagged with the evidence code ECO:0000256 (sequence model evidence used in automatic assertion) and source SAM:MobiDB-lite. Entries with disordered regions can be retrieved using these queries:

annotation:(type:region disordered) AND reviewed:yes
annotation:(type:compbias) AND reviewed:yes

In cases where there is experimental evidence for intrinsically disordered regions, curators can modify the predicted results, or add new expert-curated regions, using the appropriate experimental evidence attribution.

Predictions from the MobiDB-lite method are also available for protein sequences in UniProtKB/TrEMBL - tagged with the same evidence code and source as in reviewed entries. They can be obtained by using these queries:

annotation:(type:region disordered) AND reviewed:no
annotation:(type:compbias) AND reviewed:no

See also:

• SAM - Sequence Analysis Methods for automatic annotation

Changes to the controlled vocabulary of human diseases

New diseases:

• Albinism, oculocutaneous, 8
• AMED syndrome, digenic
• Amyotrophic lateral sclerosis 26, with or without frontotemporal dementia
• Blistering, acantholytic, of oral and laryngeal mucosa
• Carpal tunnel syndrome 2
• Chorioretinal atrophy, progressive bifocal
• Deafness, autosomal recessive, 117
• Deafness, congenital, and adult-onset progressive leukoencephalopathy
• Developmental and epileptic encephalopathy 90
• Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy
• ENDOVE syndrome, limb-brain type
• ENDOVE syndrome, limb-only type
• Epilepsy, progressive myoclonic 12
• Erythrokeratodermia variabilis et progressiva 7
• Frontotemporal dementia and/or amyotrophic lateral sclerosis 5
• Frontotemporal dementia and/or amyotrophic lateral sclerosis 8
• Gastric adenocarcinoma and proximal polyposis of the stomach
• Hermansky-Pudlak syndrome 11
• Immunodeficiency 76
• Intellectual developmental disorder, autosomal dominant 64
• Intellectual developmental disorder with paroxysmal dyskinesia or seizures
• Joubert syndrome 37
• Leber hereditary optic neuropathy modifier
• Lessel-Kreienkamp syndrome
• Leukoencephalopathy, progressive, infantile-onset, with or without deafness
• Li-Campeau syndrome
• Macroglobulinemia, Waldenstrom, 1
• Mental retardation, X-linked 50
• Microcephaly 26, primary, autosomal dominant
• Microcephaly 27, primary, autosomal dominant
• Mitochondrial complex I deficiency, nuclear type 36
• Mitochondrial complex II deficiency, nuclear type 2
• Mitochondrial complex II deficiency, nuclear type 3
• Mitochondrial complex II deficiency, nuclear type 4
• Multiple congenital anomalies-neurodevelopmental syndrome, X-linked
• Myopathy, myofibrillar, 11
• Nephrotic syndrome 22
• Nephrotic syndrome 23
• Neurodegeneration, childhood-onset, with hypotonia, respiratory insufficiency, and brain imaging abnormalities
• Neurodevelopmental disorder with or without early-onset generalized epilepsy
• Neurofacioskeletal syndrome with or without renal agenesis
• Neuropathy, hereditary motor, with myopathic features
• Oculomotor-abducens synkinesis
• Olmsted syndrome 2
• Oocyte maturation defect 10
• Premature ovarian failure 18
• Proteasome-associated autoinflammatory syndrome 4
• Proteasome-associated autoinflammatory syndrome 5
• Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2
• Spermatogenic failure, X-linked, 3
• Spermatogenic failure 51
• Spermatogenic failure 52
• Sulfide:quinone oxidoreductase deficiency
• Vertebral, cardiac, tracheoesophageal, renal, and limb defects

Modified diseases:

• Amyotrophic lateral sclerosis 12 -> Amyotrophic lateral sclerosis 12 with or without frontotemporal dementia
• Amyotrophic lateral sclerosis 14, with or without frontotemporal dementia -> Frontotemporal dementia and/or amyotrophic lateral sclerosis 6
• Birk-Barel mental retardation dysmorphism syndrome -> Birk-Barel syndrome
• COACH syndrome -> COACH syndrome 1
• Diabetes mellitus, permanent neonatal 1 -> Diabetes mellitus, permanent neonatal, 1
• Diabetes mellitus, permanent neonatal 2 -> Diabetes mellitus, permanent neonatal, 2
• Diabetes mellitus, permanent neonatal 3 -> Diabetes mellitus, permanent neonatal, 3
• Diabetes mellitus, permanent neonatal 4 -> Diabetes mellitus, permanent neonatal, 4
• Epileptic encephalopathy, early infantile, 57 -> Developmental and epileptic encephalopathy 57
• Epileptic encephalopathy, early infantile, 85, with or without midline brain defects -> Developmental and epileptic encephalopathy 85 with or without midline brain defects
• Frontotemporal dementia, chromosome 3-linked -> Frontotemporal dementia and/or amyotrophic lateral sclerosis 7
• Generalized thyroid hormone resistance -> Thyroid hormone resistance, generalized, autosomal dominant
• Generalized thyroid hormone resistance autosomal recessive -> Thyroid hormone resistance, generalized, autosomal recessive
• Hemophagocytic lymphohistiocytosis, familial, 6 -> Immune dysregulation and systemic hyperinflammation syndrome
• Intellectual developmental disorder 59 -> Intellectual developmental disorder, autosomal dominant 59
• Intellectual developmental disorder 60 with seizures -> Intellectual developmental disorder, autosomal dominant 60, with seizures
• Intellectual developmental disorder 61 -> Intellectual developmental disorder, autosomal dominant 61
• Intellectual developmental disorder 62 -> Intellectual developmental disorder, autosomal dominant 62
• Mental retardation, autosomal recessive 15 -> Rafiq syndrome
• Methylmalonic aciduria type mut -> Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency
• Mitochondrial complex II deficiency -> Mitochondrial complex II deficiency, nuclear type 1
• Neurodevelopmental disorder with alopecia and brain abnormalities -> Bachmann-Bupp syndrome
• Vasculopathy, retinal, with cerebral leukodystrophy -> Vasculopathy, retinal, with cerebral leukoencephalopathy and systemic manifestations

Deleted disease

• Amyotrophic lateral sclerosis 17

Changes to the controlled vocabulary for PTMs

New term for the feature key 'Glycosylation' ('CARBOHYD' in the flat file):

• N-alpha-linked (Rha) arginine

Modified term for the feature key 'Glycosylation' ('CARBOHYD' in the flat file):

• N-linked (GlcNAc) arginine -> N-beta-linked (GlcNAc) arginine

Changes in subcellular location controlled vocabulary

New subcellular locations:

• Bacterial microcompartment
• Cytolytic granule
• Cytolytic granule lumen
• Cytolytic granule membrane
• Zymogen granule
• Zymogen granule lumen
• Zymogen granule membrane

Changes to keywords

New keyword:

• Bacterial microcompartment

Headline

With a little help from my friend

One of the early responses to eukaryotic DNA damage is ADP-ribosylation of histones and other proteins in the vicinity of the lesion. This post-translation modification, which is important for the decompaction of chromatin and the recruitment of repair factors, can be catalyzed by two related enzymes: PARP1 or PARP2. In the absence of binding partners, the PARPs catalyze ADP-ribosylation on aspartate or glutamate residues. However, in the context of DNA damage, ADP-ribosylation predominantly occurs on serine residues. The switch in amino acid specificity requires the presence of a protein cofactor HPF1. Its mechanism was unraveled recently through the study of the X-ray crystal structure of the PARP2-HPF1 complex.

Under resting, or low stress conditions, the interaction between PARP1 or PARP2 and HPF1 is limited by an inhibitory domain in PARP. In response to high and acute levels of DNA damage, PARP binds DNA and undergoes conformational changes, the inhibitory domain is unfolded, and the interaction with HPF1 is stabilized. Within the complex, PARP2 and HPF1 form a new joint active site with an HPF1 glutamate residue positioned at the very core of the enzyme. Mutagenesis of this glutamate residue to alanine does not affect HPF1 binding to PARP2, but does impair serine ADP-ribosylation. This glutamate within the active site is thought to allow the deprotonation of the serine residue, making it a favorable target for nucleophilic attack. This step is dispensable when the substrate is an aspartate or glutamate residue that is deprotonated at neutral pH. In addition to its active role in catalysis per se, HPF1 may also participate in substrate recognition. Indeed, a putative peptide-binding canyon may form at the interface of HPF1 and PARP2. This site seems perfectly suited for binding lysine-serine motifs that are highly enriched among serine-ADP-ribosylation substrates in vivo.

This discovery goes beyond the excitement of unraveling a new mechanism in a crucial process in DNA repair. It may also have an impact in a clinical setting. PARP small inhibitors have been approved for the treatment of BRCA-negative breast, ovarian and fallopian tube cancers, and it has been previously shown that human cells lacking HPF1 exhibit sensitivity to DNA damaging agents and PARP inhibition. Therefore it may be of interest to re-evaluate the potency and selectivity of existing PARP inhibitors in the presence of HPF1-PARP1/2 complexes and to develop new drugs that would specifically interfere with HPF1-mediated PARP1/2 activity, but not with PARP1/2 enzymatic activity on non-serine residues.

As of this release, HPF1, PARP1 and PARP2 entries have been updated and are publicly available.

UniProt website news

Visualization of subcellular location annotation using SwissBioPics

As of this release, we are using the SwissBioPics library of interactive biological images for the visualization of subcellular location data to enhance the representation of UniProt and Gene Ontology (GO) subcellular location annotations.

SwissBioPics covers cell types from all kingdoms of life - ranging from muscle, neuronal and epithelial cells of animals, to the rods, cocci, clubs, spirals and other more exotic forms of bacteria and archaea. A reusable web component and an API allow website developers to visualize subcellular location data (in the form of GO cellular component or UniProt subcellular location identifiers) on these images. The code and technical documentation are available at npmjs.com.

Examples:

• Magnetosome formation protease MamE from M.magneticum
• Spore membrane assembly protein 2 from S.cerevisiae
• Potassium voltage-gated channel subfamily D member 2 from H.sapiens

UniProtKB news

Change of evidence codes for combinatorial evidence

When UniProt adopted the Evidence Code Ontology (ECO) in 2014, we chose to use the concepts ECO:0000244 in manual assertions and ECO:0000213 in automatic assertions, respectively, for information inferred from a combination of experimental and computational evidence. These two ECO concepts have in fact a broader meaning that includes combinations of any type of evidence, and meanwhile the ECO has been extended with concepts that exactly reflect our usage. We have therefore replaced ECO:0000244 by ECO:0007744 and ECO:0000213 by ECO:0007829.

Changes to the controlled vocabulary of human diseases

New diseases:

• Arthrogryposis, distal, 1C
• Cardioacrofacial dysplasia 1
• Cardioacrofacial dysplasia 2
• Cardiofacioneurodevelopmental syndrome
• Cleft palate, proliferative retinopathy, and developmental delay
• COACH syndrome 2
• COACH syndrome 3
• Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1
• Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2
• Combined oxidative phosphorylation deficiency 51
• Deafness, autosomal dominant, 78
• Deafness, autosomal dominant, 79
• Deafness, autosomal recessive, 116
• Delpire-McNeill syndrome
• Developmental and epileptic encephalopathy 89
• Focal segmental glomerulosclerosis 10
• Immunodeficiency 75
• Inflammatory bowel disease 30
• Intellectual developmental disorder with speech delay and axonal peripheral neuropathy
• Kaya-Barakat-Masson syndrome
• Kilquist syndrome
• Leukodystrophy, hypomyelinating, 20
• Mandibuloacral dysplasia progeroid syndrome
• Microcornea, rod-cone dystrophy, cataract, and posterior staphyloma 1
• Mismatch repair cancer syndrome 2
• Mismatch repair cancer syndrome 3
• Mismatch repair cancer syndrome 4
• Mitochondrial complex IV deficiency, nuclear type 1
• Mitral valve prolapse 3
• Monosomy 7 myelodysplasia and leukemia syndrome 1
• Monosomy 7 myelodysplasia and leukemia syndrome 2
• Mucoepithelial dysplasia, hereditary
• Neurodevelopmental disorder with alopecia and brain abnormalities
• Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities
• Neurodevelopmental disorder with dysmorphic facies, sleep disturbance, and brain abnormalities
• Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities
• Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities
• Neurodevelopmental disorder with microcephaly, seizures, and brain atrophy
• Neurodevelopmental disorder with seizures and brain atrophy
• Neurodevelopmental disorder with speech impairment and dysmorphic facies
• Neuronopathy, distal hereditary motor, 5C
• Nivelon-Nivelon-Mabille syndrome
• Noonan syndrome 13
• Osteogenesis imperfecta 21
• Premature ovarian failure 17
• Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndrome
• Ritscher-Schinzel syndrome 3
• Spermatogenic failure 45
• Spermatogenic failure 46
• Spermatogenic failure 47
• Spermatogenic failure 48
• Spermatogenic failure 49
• Spermatogenic failure 50
• Thrombocytopenia 7
• Vertebral hypersegmentation and orofacial anomalies
• VEXAS syndrome
• Vitamin D-dependent rickets 3

Modified diseases:

• Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1 -> Mitochondrial complex IV deficiency, nuclear type 2
• Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2 -> Mitochondrial complex IV deficiency, nuclear type 6
• Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 3 -> Mitochondrial complex IV deficiency, nuclear type 9
• Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 4 -> Mitochondrial complex IV deficiency, nuclear type 13
• Epileptic encephalopathy, early infantile, 1 -> Developmental and epileptic encephalopathy 1
• Epileptic encephalopathy, early infantile, 2 -> Developmental and epileptic encephalopathy 2
• Epileptic encephalopathy, early infantile, 3 -> Developmental and epileptic encephalopathy 3
• Epileptic encephalopathy, early infantile, 4 -> Developmental and epileptic encephalopathy 4
• Epileptic encephalopathy, early infantile, 5 -> Developmental and epileptic encephalopathy 5
• Epileptic encephalopathy, early infantile, 6 -> Dravet syndrome
• Epileptic encephalopathy, early infantile, 7 -> Developmental and epileptic encephalopathy 7
• Epileptic encephalopathy, early infantile, 8 -> Developmental and epileptic encephalopathy 8
• Epileptic encephalopathy, early infantile, 9 -> Developmental and epileptic encephalopathy 9
• Epileptic encephalopathy, early infantile, 11 -> Developmental and epileptic encephalopathy 11
• Epileptic encephalopathy, early infantile, 12 -> Developmental and epileptic encephalopathy 12
• Epileptic encephalopathy, early infantile, 13 -> Developmental and epileptic encephalopathy 13
• Epileptic encephalopathy, early infantile, 14 -> Developmental and epileptic encephalopathy 14
• Epileptic encephalopathy, early infantile, 15 -> Developmental and epileptic encephalopathy 15
• Epileptic encephalopathy, early infantile, 16 -> Developmental and epileptic encephalopathy 16
• Epileptic encephalopathy, early infantile, 17 -> Developmental and epileptic encephalopathy 17
• Epileptic encephalopathy, early infantile, 18 -> Developmental and epileptic encephalopathy 18
• Epileptic encephalopathy, early infantile, 19 -> Developmental and epileptic encephalopathy 19
• Epileptic encephalopathy, early infantile, 21 -> Developmental and epileptic encephalopathy 21
• Epileptic encephalopathy, early infantile, 23 -> Developmental and epileptic encephalopathy 23
• Epileptic encephalopathy, early infantile, 24 -> Developmental and epileptic encephalopathy 24
• Epileptic encephalopathy, early infantile, 25, with amelogenesis imperfecta -> Developmental and epileptic encephalopathy 25, with amelogenesis imperfecta
• Epileptic encephalopathy, early infantile, 26 -> Developmental and epileptic encephalopathy 26
• Epileptic encephalopathy, early infantile, 27 -> Developmental and epileptic encephalopathy 27
• Epileptic encephalopathy, early infantile, 28 -> Developmental and epileptic encephalopathy 28
• Epileptic encephalopathy, early infantile, 29 -> Developmental and epileptic encephalopathy 29
• Epileptic encephalopathy, early infantile, 30 -> Developmental and epileptic encephalopathy 30
• Epileptic encephalopathy, early infantile, 31 -> Developmental and epileptic encephalopathy 31
• Epileptic encephalopathy, early infantile, 32 -> Developmental and epileptic encephalopathy 32
• Epileptic encephalopathy, early infantile, 33 -> Developmental and epileptic encephalopathy 33
• Epileptic encephalopathy, early infantile, 34 -> Developmental and epileptic encephalopathy 34
• Epileptic encephalopathy, early infantile, 35 -> Developmental and epileptic encephalopathy 35
• Epileptic encephalopathy, early infantile, 36 -> Developmental and epileptic encephalopathy 36
• Epileptic encephalopathy, early infantile, 37 -> Developmental and epileptic encephalopathy 37
• Epileptic encephalopathy, early infantile, 38 -> Developmental and epileptic encephalopathy 38
• Epileptic encephalopathy, early infantile, 39 -> Developmental and epileptic encephalopathy 39
• Epileptic encephalopathy, early infantile, 40 -> Developmental and epileptic encephalopathy 40
• Epileptic encephalopathy, early infantile, 41 -> Developmental and epileptic encephalopathy 41
• Epileptic encephalopathy, early infantile, 42 -> Developmental and epileptic encephalopathy 42
• Epileptic encephalopathy, early infantile, 43 -> Developmental and epileptic encephalopathy 43
• Epileptic encephalopathy, early infantile, 44 -> Developmental and epileptic encephalopathy 44
• Epileptic encephalopathy, early infantile, 45 -> Developmental and epileptic encephalopathy 45
• Epileptic encephalopathy, early infantile, 46 -> Developmental and epileptic encephalopathy 46
• Epileptic encephalopathy, early infantile, 47 -> Developmental and epileptic encephalopathy 47
• Epileptic encephalopathy, early infantile, 48 -> Developmental and epileptic encephalopathy 48
• Epileptic encephalopathy, early infantile, 49 -> Developmental and epileptic encephalopathy 49
• Epileptic encephalopathy, early infantile, 50 -> evelopmental and epileptic encephalopathy 50
• Epileptic encephalopathy, early infantile, 51 -> Developmental and epileptic encephalopathy 51
• Epileptic encephalopathy, early infantile, 52 -> Developmental and epileptic encephalopathy 52
• Epileptic encephalopathy, early infantile, 53 -> Developmental and epileptic encephalopathy 53
• Epileptic encephalopathy, early infantile, 54 -> Developmental and epileptic encephalopathy 54
• Epileptic encephalopathy, early infantile, 55 -> Developmental and epileptic encephalopathy 55
• Epileptic encephalopathy, early infantile, 56 -> Developmental and epileptic encephalopathy 56
• Epileptic encephalopathy, early infantile, 58 -> Developmental and epileptic encephalopathy 58
• Epileptic encephalopathy, early infantile, 59 -> Developmental and epileptic encephalopathy 59
• Epileptic encephalopathy, early infantile, 60 -> Developmental and epileptic encephalopathy 60
• Epileptic encephalopathy, early infantile, 61 -> Developmental and epileptic encephalopathy 61
• Epileptic encephalopathy, early infantile, 62 -> Developmental and epileptic encephalopathy 62
• Epileptic encephalopathy, early infantile, 63 -> Developmental and epileptic encephalopathy 63
• Epileptic encephalopathy, early infantile, 64 -> Developmental and epileptic encephalopathy 64
• Epileptic encephalopathy, early infantile, 65 -> Developmental and epileptic encephalopathy 65
• Epileptic encephalopathy, early infantile, 66 -> Developmental and epileptic encephalopathy 66
• Epileptic encephalopathy, early infantile, 67 -> Developmental and epileptic encephalopathy 67
• Epileptic encephalopathy, early infantile, 68 -> Developmental and epileptic encephalopathy 68
• Epileptic encephalopathy, early infantile, 69 -> Developmental and epileptic encephalopathy 69
• Epileptic encephalopathy, early infantile, 70 -> Developmental and epileptic encephalopathy 70
• Epileptic encephalopathy, early infantile, 71 -> Developmental and epileptic encephalopathy 71
• Epileptic encephalopathy, early infantile, 72 -> Developmental and epileptic encephalopathy 72
• Epileptic encephalopathy, early infantile, 73 -> Developmental and epileptic encephalopathy 73
• Epileptic encephalopathy, early infantile, 74 -> Developmental and epileptic encephalopathy 74
• Epileptic encephalopathy, early infantile, 75 -> Developmental and epileptic encephalopathy 75
• Epileptic encephalopathy, early infantile, 76 -> Developmental and epileptic encephalopathy 76
• Epileptic encephalopathy, early infantile, 78 -> Developmental and epileptic encephalopathy 78
• Epileptic encephalopathy, early infantile, 79 -> Developmental and epileptic encephalopathy 79
• Epileptic encephalopathy, early infantile, 80 -> Developmental and epileptic encephalopathy 80
• Epileptic encephalopathy, early infantile, 81 -> Developmental and epileptic encephalopathy 81
• Epileptic encephalopathy, early infantile, 82 -> Developmental and epileptic encephalopathy 82
• Epileptic encephalopathy, early infantile, 83 -> Developmental and epileptic encephalopathy 83
• Epileptic encephalopathy, early infantile, 84 -> Developmental and epileptic encephalopathy 84
• Epileptic encephalopathy, early infantile, 86 -> Developmental and epileptic encephalopathy 86
• Epileptic encephalopathy, early infantile, 87 -> Developmental and epileptic encephalopathy 87
• Epileptic encephalopathy, early infantile, 88 -> Developmental and epileptic encephalopathy 88
• Leigh syndrome French-Canadian type -> Mitochondrial complex IV deficiency, nuclear type 5

Changes to the controlled vocabulary for PTMs

New terms for the feature key 'Modified residue' ('MOD_RES' in the flat file):

• O-di-AMP-tyrosine
• O-tri-AMP-tyrosine
• 5-glutamyl dopamine
• 5-glutamyl noradrenaline
• 5-glutamyl serotonin

Modified term for the feature key 'Modified residue' ('MOD_RES' in the flat file):

• L-isoglutamyl histamine -> 5-glutamyl histamine

Changes in subcellular location controlled vocabulary

New subcellular locations:

• Cortical granule
• Dynein axonemal particle
• Spore
• Zona pellucida

Modified subcellular location:

• Postsynaptic Golgi apparatus -> Golgi outpost
• Spore core membrane -> Spore membrane

(Almost) all about that CBASS

Bacteria and archaea, like every other living organisms, must defend themselves against viral (bacteriophage or phage) attack. It is estimated that there are 10³¹ bacteriophages on the planet found in all habitats; sea water, animal gastrointestinal tracts, oceanic basement... A number of anti-phage defense mechanisms are known: restriction nucleases, an Argonaute-like system, CRISPR, and more are being discovered as we explore less well-known archaea and bacteria. A new phage defense mechanism has been recently discovered and is being characterized, the CBASS system (Cyclic oligonucleotide-Based Anti-phage Signalling System).

At the heart of each CBASS system is a cyclic nucleotide synthase. These belong to the cGAS/DncV-like nucleotidyltransferase family (abbreviated CD-NTase), and they make cyclic di-, tri-, and possibly even tetranucleotides. The cyclic nucleotides activate an effector protein, encoded adjacently to the CD-NTase. The effectors have a variety of activities: nucleases that degrade all DNA, including viral DNA (NucC, Cap4), an NAD+ hydrolase that presumably depletes cellular NAD+ (Cap12), phospholipases that are capable of degrading the cell membrane (CapV, CapE), and transmembrane proteins that may form pores (Cap13) have all been observed, although not all have been characterized yet.

Transforming CBASS into bacteria without a natural CBASS system protects the population against phages. The effectors lead to cell death before the phage have completed an infection cycle, thus protecting adjacent uninfected cells from infection. There are at least 4 types of CBASS systems, classified on basis of the presence or absence of ancillary genes encoded in the same locus. Type I systems have no extra genes. In type II systems, the ancillary proteins Cap2 and Cap3 are not necessary for protection against all phages, but they enlarge the range of phages against which the system is active. In type III systems, the ancillary proteins Cap6 and Cap7 control the activity of the system; Cap7 is required to activate the CD-NTase, while Cap6 prevents the Cap7-CD-NTase association. A subtype has a second Cap7-like gene called Cap8 which may act as a scaffold for complex assembly. Type IV systems are rare and so far uncharacterized. They occur mostly in Firmicutes and archaea.

At the request of Dr. Philip Kranzusch, the lead author on many of these papers, characterized CBASS proteins have been annotated. We'd like to thank Dr. Kranzusch, members of his lab, and Dr. R. Sorek for answering annotation questions. We also thank you for your interest in our knowledgebase and remind you that we are always looking for your input on our entries.

UniProtKB news

Change of the cross-references to EuPathDB: renamed to VEuPathDB

We have updated our cross-references to reflect the name change of EuPathDB into VEuPathDB, following the inclusion of genomes of invertebrate vectors of human pathogens.

Removal of the cross-references to VectorBase

Direct cross-references to VectorBase have been removed, as VectorBase is now part of the VEuPathDB resources.

Removal of the cross-references to UniCarbKB

Cross-references to UniCarbKB have been removed.

Changes to the controlled vocabulary of human diseases

New diseases:

• Autoinflammation, immune dysregulation, and eosinophilia
• Coenzyme Q10 deficiency, primary, 9
• Combined oxidative phosphorylation deficiency 48
• Combined oxidative phosphorylation deficiency 49
• Combined oxidative phosphorylation deficiency 50
• DEEAH syndrome
• Hemophagocytic lymphohistiocytosis, familial, 6
• Ichthyosis, lamellar, autosomal dominant
• IFAP syndrome 2
• Immunodeficiency 73B with defective neutrophil chemotaxis and lymphopenia
• Immunodeficiency 73C with defective neutrophil chemotaxis and hypogammaglobulinemia
• Intellectual developmental disorder, X-linked, syndromic, Armfield type
• Intellectual developmental disorder with seizures and language delay
• Intellectual developmental disorder with epilepsy, behavioral abnormalities, and coarse facies
• Mitochondrial complex I deficiency, nuclear type 35
• Mitochondrial complex IV deficiency, nuclear type 3
• Mitochondrial complex IV deficiency, nuclear type 4
• Mitochondrial complex IV deficiency, nuclear type 7
• Mitochondrial complex IV deficiency, nuclear type 8
• Mitochondrial complex IV deficiency, nuclear type 10
• Mitochondrial complex IV deficiency, nuclear type 11
• Mitochondrial complex IV deficiency, nuclear type 12
• Mitochondrial complex IV deficiency, nuclear type 14
• Mitochondrial complex IV deficiency, nuclear type 15
• Mitochondrial complex IV deficiency, nuclear type 16
• Mitochondrial complex IV deficiency, nuclear type 17
• Mitochondrial complex IV deficiency, nuclear type 18
• Mitochondrial complex IV deficiency, nuclear type 19
• Mitochondrial complex IV deficiency, nuclear type 20
• Mitochondrial complex IV deficiency, nuclear type 21
• Muscular dystrophy-dystroglycanopathy congenital with impaired intellectual development B15
• Myopathy, epilepsy, and progressive cerebral atrophy
• Myopathy, myofibrillar, 10
• Neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia
• Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities
• Oocyte maturation defect 8
• Oocyte maturation defect 9
• Optic atrophy 13 with retinal and foveal abnormalities
• Pallister-Hall-like syndrome
• Rajab interstitial lung disease with brain calcifications 2
• Retinitis pigmentosa 90
• Spastic paraplegia 83, autosomal recessive
• Spermatogenic failure 44
• Spinal muscular atrophy, infantile, James type
• Vissers-Bodmer syndrome

Modified diseases:

• Familial hemophagocytic lymphohistiocytosis 2 -> Hemophagocytic lymphohistiocytosis, familial, 2
• Familial hemophagocytic lymphohistiocytosis 3 -> Hemophagocytic lymphohistiocytosis, familial, 3
• Familial hemophagocytic lymphohistiocytosis 4 -> Hemophagocytic lymphohistiocytosis, familial, 4
• Familial hemophagocytic lymphohistiocytosis 5 -> Hemophagocytic lymphohistiocytosis, familial, 5
• Neutrophil immunodeficiency syndrome -> Immunodeficiency 73A with defective neutrophil chemotaxis and leukocytosis

Changes in subcellular location controlled vocabulary

New subcellular locations:

• Autolysosome
• Autolysosome membrane
• Autolysosome lumen
• Ascus epiplasm

Changes to the humsavar.txt file and related keywords

The humsavar.txt file lists all missense variants annotated in UniProtKB/Swiss-Prot human entries. It provides a variant classification which is intended for research purposes only, not for clinical and diagnostic use. Variants were previously classified into the categories Disease, Polymorphisms and Unclassified. We have renamed these categories to follow the terminology recommended by the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) (Richards et al. PubMed:25741868):

Previous category	New category	Description
Disease	LP/P	likely pathogenic or pathogenic
Polymorphism	LB/B	likely benign or benign
Unclassified	US	uncertain significance

Previous format:

Main      Swiss-Prot             AA             Type of
gene name AC         FTId        change         variant       dbSNP          Disease name
_________ __________ ___________ ______________ _____________ ______________ _____________________
...
CC2D2A    Q9P2K1     VAR_075698  p.Trp1182Arg   Disease       rs386833755    Joubert syndrome 9 (JBTS9) [MIM:612285]
CC2D2A    Q9P2K1     VAR_076881  p.Ser117Arg    Unclassified  rs186264635    Joubert syndrome 9 (JBTS9) [MIM:612285]
CC2D2A    Q9P2K1     VAR_076882  p.Lys507Glu    Polymorphism  rs144439937    Joubert syndrome 9 (JBTS9) [MIM:612285]
...

New format:

Main      Swiss-Prot             AA             Variant
gene name AC         FTId        change         category dbSNP          Disease name
_________ __________ ___________ ______________ ________ ______________ _____________________
...
CC2D2A    Q9P2K1     VAR_075698  p.Trp1182Arg   LP/P     rs386833755    Joubert syndrome 9 (JBTS9) [MIM:612285]
CC2D2A    Q9P2K1     VAR_076881  p.Ser117Arg    US       rs186264635    Joubert syndrome 9 (JBTS9) [MIM:612285]
CC2D2A    Q9P2K1     VAR_076882  p.Lys507Glu    LB/B     rs144439937    Joubert syndrome 9 (JBTS9) [MIM:612285]
...

Also in line with the ACMG/AMP guidelines, we have at the same time deprecated the keyword "Polymorphism" and renamed the keyword "Disease mutation" to "Disease variant". This was done because the terms 'polymorphism' and 'mutation', which have been widely used, often lead to confusion due to incorrect assumptions of pathogenic and benign effects, respectively.

Entries with variant annotations can be retrieved on the UniProt website with the query annotation:(type:variant).

UniProt FTP and website news

Changes to the FTP repository for reference proteomes

We currently distribute the UniProt reference proteomes on our FTP site in four taxonomic division folders (Archaea, Bacteria, Eukaryota and Viruses) and provide, for each proteome, its sequences in FASTA format and mappings from UniProt identifiers and gene names to those found in other databases. Starting from this release, we also publish the full protein records for a proteome in the UniProtKB text and XML format, and we have at the same time introduced a subfolder for each proteome that groups all its files in order to reduce the number of files in the taxonomic division folders.

Example: UP000005640

Previous FTP folder and files:

https://ftp.uniprot.org/pub/databases/uniprot/current_release/knowledgebase/reference_proteomes/Eukaryota/

• UP000005640_9606.fasta.gz
• UP000005640_9606_additional.fasta.gz
• UP000005640_9606_DNA.fasta.gz
• UP000005640_9606_DNA.miss.gz
• UP000005640_9606.idmapping.gz
• UP000005640_9606.gene2acc.gz

New FTP folder and files:

https://ftp.uniprot.org/pub/databases/uniprot/current_release/knowledgebase/reference_proteomes/Eukaryota/UP000005640/

• UP000005640_9606.dat.gz — UniProtKB text format
• UP000005640_9606.xml.gz — UniProtKB XML format
• UP000005640_9606.fasta.gz
• UP000005640_9606_additional.fasta.gz
• UP000005640_9606_DNA.fasta.gz
• UP000005640_9606_DNA.miss.gz
• UP000005640_9606.idmapping.gz
• UP000005640_9606.gene2acc.gz

Browser support change: End of support for Microsoft Internet Explorer

We have phased out support for Microsoft's Internet Explorer (IE 11), since our user base for this web browser is continuously decreasing and has significantly fallen below 1.5%. Please switch to a more recent and supported browser in order to enjoy the full functionalities of the UniProt website.

Even if you are not using IE 11, it may be a good idea to look at the list of the browsers we support and consider switching to the most recent version of your browser for the best user experience and security.

Headline

Venoms, gold mines for new antiprotozoal drugs

Neglected diseases are typically tropical infections, which are common in low-income populations in developing regions of Africa, Asia, and the Americas and affect more than one billion people. Among them, Chagas disease, also known as American trypanosomiasis, affects an estimated 6 to 7 million people worldwide. This disease is caused by the parasitic protozoan Trypanosoma cruzi. The disease is typically transmitted to humans and other mammals by the bite of infected triatomine insects, also known as kissing bugs or vampire bugs. Once inside the host, the protozoan invades cells near the site of inoculation, where it differentiates into an intracellular parasitic form called the amastigote. Amastigotes multiply, differentiate into trypomastigotes which burst the host cell, and are released into the circulation, from where they can invade a variety of tissues and repeat the same infectious cycle in new sites. In the early stage of infection, symptoms are mild, if any, and may include fever, swollen lymph nodes, headaches, or swelling at the site of the bite. After a few weeks, untreated individuals enter the chronic phase of disease and most do not show any further symptoms. However, in the long term (10-30 years after the initial illness), chronic infection may lead to cardiomyopathies, digestive tract pathologies, and up to 10% of people experience nerve damage.

There are only two drugs currently used to treat Chagas disease, benznidazole and nifurtimox. Unfortunately they are rarely beneficial during the chronic phase of the disease and can cause severe adverse effects. Moreover, resistance to these drugs is emerging in various parasitic strains. In this context, the observation that crude venom from a Brazilian ant called Dinoponera quadriceps had antichagasic activity and low toxicity in vitro offers one hope for the development of alternative therapies for Chagas disease. A venom component bearing this activity was identified as a 23-amino acid long peptide, called M-poneratoxin-Dq3a (M-PONTX-Dq3a). This peptide induced trypanosome necrosis and acted on the three parasitic forms: epimastigote (found in the gut of the vector insect), infectious trypomastigote and intracellular amastigote, suggesting that M-PONTX-Dq3a could be beneficial during the chronic phase of the infection. These effects were observed at concentrations low enough to avoid any toxicity for mammalian host cells contrary to benznidazole.

Ants are not the only organisms that can give us a hand in the fight against T. cruzi. Snakes, such as Bothrops atrox and Crotalus durissus terrificus, and wasps, such as Polybia paulista, have also been shown to produce antichagasic toxins. All venom toxins characterized so far were active against the three T. cruzi forms at concentrations that did not harm host cells. Their modes of action could differ, but all exhibited a high selectivity index (a ratio that measures the window between cytotoxicity and antimicrobial activity), which clearly qualifies them for further study in the development of new drugs.

Animal toxins with antichagasic properties have been manually annotated in UniProtKB/Swiss-Prot and are publicly available as of this release.

UniProtKB news

Removal of the cross-references to KO

Cross-references to KO (KEGG Orthology) have been removed.

Changes to the controlled vocabulary of human diseases

New diseases:

• Arthrogryposis multiplex congenita 5
• Combined oxidative phosphorylation deficiency 45
• Combined oxidative phosphorylation deficiency 46
• Combined oxidative phosphorylation deficiency 47
• Cone-rod synaptic disorder syndrome, congenital non-progressive
• Epileptic encephalopathy, early infantile, 88
• Episodic ataxia 9
• Granulomatous disease, chronic, autosomal recessive, 5
• Growth hormone insensitivity syndrome with immune dysregulation 2, autosomal dominant
• Heterotaxy, visceral, 9, autosomal, with male infertility
• Hyper-IgE recurrent infection syndrome 5, autosomal recessive
• Immunodeficiency 69
• Immunodeficiency 70
• Immunodeficiency 72 with autoinflammation
• Immunodeficiency 74, COVID19-related, X-linked
• Li-Ghorbani-Weisz-Hubshman syndrome
• Mitchell syndrome
• Mitochondrial DNA depletion syndrome 19
• Myopathy, congenital, with diaphragmatic defects, respiratory insufficiency, and dysmorphic facies
• Neurodegeneration, infantile-onset, biotin-responsive
• Neurodevelopmental disorder with seizures, hypotonia, and brain imaging abnormalities
• Oculopharyngodistal myopathy 2
• Optic atrophy 12
• Periodic fever, immunodeficiency, and thrombocytopenia syndrome
• Retinitis pigmentosa 32
• Retinitis pigmentosa 89
• Spondylometaphyseal dysplasia with corneal dystrophy
• Suleiman-El-Hattab syndrome
• Tolchin-Le Caignec syndrome
• Treacher Collins syndrome 4
• Warfarin sensitivity, X-linked

Modified diseases:

• Arthrogryposis multiplex congenita, neurogenic, with agenesis of the corpus callosum -> Arthrogryposis multiplex congenita 4, neurogenic, with agenesis of the corpus callosum
• Deafness, autosomal dominant, 1 -> Deafness, autosomal dominant 1, with or without thrombocytopenia
• Neuromuscular disease and ocular or auditory anomalies with or without seizures -> Neuromuscular oculoauditory syndrome
• Short stature, brachydactyly, intellectual developmental disability, and seizures -> Short stature, brachydactyly, impaired intellectual developmental, and seizures

Headline

PCK1 vacillating between gluconeogenesis and lipogenesis

Lipid metabolism is a tightly regulated process, which relies on sterol regulatory element-binding (SREBPs) transcription factors for the activation of genes involved in the synthesis of fatty acids, triglycerides, and cholesterol. In resting conditions, when the levels of cholesterol are sufficient, SREBPs are present as precursors in the endoplasmic reticulum (ER) membrane in complex with a protein called SCAP. SCAP also interacts with a member of the ER resident INSIG protein family. The interaction with INSIG ensures that the SCAP-SREBP complex is retained in the ER. When cholesterol levels drop, INSIG and SCAP no longer bind and the SCAP-SREBP complex is transported to the Golgi apparatus, where SREBP is cleaved and its cytosolic N-terminal transcription factor domain is freed to translocate to the nucleus and activate transcription.

There are cells, however, that do not bother about regulation and just desperately need lipogenesis to proliferate. These are cancer cells. How do they achieve the synthesis of enough lipids in normal sterol levels, in conditions in which lipogenesis would normally be inhibited? The answer came from a study in hepatocellular carcinoma (HCC) cell lines. In these cells, activation with IGF1, a stimulus critical for HCC development, leads to a cascade of phosphorylation, which starts with AKT1. Activated AKT1 in turn phosphorylates PCK1, which is then translocated from the cytosol to the ER and phosphorylates INSIG. This impairs INSIG binding to the SCAP-SREBP complex, resulting in the release of the complex from the ER to the Golgi apparatus, with subsequent SERBP activation.

The discovery of PCK1 involvement in this process comes as a surprise. PCK1 is not known to be involved in lipogenesis regulation, nor to have a kinase activity. It is a rate-limiting enzyme of gluconeogenesis, a pathway that generates glucose from certain non-carbohydrate carbon substrates. In this pathway, it converts oxaloacetate into phosphoenolpyruvate. PCK1 phosphorylation by AKT1 uncovers its cryptic kinase activity and redirects it to a completely different process. Cancer cells favor glycolysis to provide energy and metabolic intermediates, and suppress gluconeogenesis. For these cells, PCK1 diversion is necessary for cell growth, as expression of a PCK1 nonphosphorylatable mutant inhibits cell proliferation, and is costless, as inhibition of gluconeogenesis is not deleterious. Although the results have been produced in HCC cells, this process may also play a role in other cancer types. Indeed, AKT1 activation has been shown in melanoma, glioblastoma and non-small cell lung carcinoma cells.

PCK1-induced activation of SREBP1 may also occur in normal hepatocytes. In mice that were refed with glucose after 24 hours of fasting, phosphorylation of AKT1, PCK1, and INSIG proteins, as well as cleavage of SREBP1, were markedly enhanced in normal liver. These observations suggest that in vivo blood glucose levels may regulate the PCK1-mediated phosphorylation of INSIG proteins and the activation of SREBP. This might point toward a potential mechanism underlying overnutrition-promoted nonalcoholic fatty liver diseases.

As of this release, proteins involved in this new regulatory pathway have been updated and are available in UniProtKB/Swiss-Prot.

UniProtKB news

Cross-references to CPTC

Cross-references have been added to CPTC, the CPTAC Antibody Portal. This portal serves as a National Cancer Institute (NCI) community resource that provides access to a large number of standardized renewable affinity reagents (to cancer-associated targets) and accompanying characterization data.

CPTC is available at https://proteomics.cancer.gov/antibody-portal.

The format of the explicit links is:

Resource abbreviation	CPTC
Resource identifier	UniProtKB accession number
Optional information 1	Number of antibodies

Example: P31751

Show all entries having a cross-reference to CPTC.

Text format

Example: P31751

DR   CPTC; P31751; 6 antibodies.

XML format

Example: P31751

<dbReference type="CPTC" id="P31751">
  <property type="antibodies" value="6 antibodies"/>
</dbReference>

RDF format

Example: P31751

uniprot:P31751
  rdfs:seeAlso <http://purl.uniprot.org/cptc/P31751> .
<http://purl.uniprot.org/cptc/P31751>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/CPTC> ;
  rdfs:comment "6 antibodies" .

Cross-references to BMRB

Cross-references have been added to the BMRB database, the Biological Magnetic Resonance Data Bank. BMRB collects, annotates, archives, and disseminates spectral and quantitative data derived from NMR spectroscopic investigations of biological macromolecules and metabolites.

BMRB is available at https://bmrb.io/.

The format of the explicit links is:

Resource abbreviation	BMRB
Resource identifier	UniProtKB accession number

Example: A1D240

Show all entries having a cross-reference to BMRB.

Text format

Example: A1D240

DR   BMRB; A1D240; -.

XML format

Example: A1D240

<dbReference type="BMRB" id="A1D240"/>

RDF format

Example: A1D240

uniprot:A1D240
  rdfs:seeAlso <http://purl.uniprot.org/bmrb/A1D240> .
<http://purl.uniprot.org/bmrb/A1D240>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/BMRB> .

Cross-references to PCDDB

Cross-references have been added to the PCDDB database, the Protein Circular Dichroism Data Bank. PCDDB is a public repository that archives and freely distributes circular dichroism (CD) and synchrotron radiation CD spectral data and their associated experimental metadata.

PCDDB is available at https://pcddb.cryst.bbk.ac.uk/.

The format of the explicit links is:

Resource abbreviation	PCDDB
Resource identifier	UniProtKB accession number

Example: Q70Q12

Show all entries having a cross-reference to PCDDB.

Text format

Example: Q70Q12

DR   PCDDB; Q70Q12; -.

XML format

Example: Q70Q12

<dbReference type="PCDDB" id="Q70Q12"/>

RDF format

Example: Q70Q12

uniprot:Q70Q12
  rdfs:seeAlso <http://purl.uniprot.org/pcddb/Q70Q12> .
<http://purl.uniprot.org/pcddb/Q70Q12>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/PCDDB> .

Cross-references to SASBDB

Cross-references have been added to the SASBDB database, the Small Angle Scattering Biological Data Bank. SASBDB is a fully searchable curated repository of freely accessible and downloadable experimental scattering data, which are deposited together with the relevant experimental conditions, sample details, derived models and their fits to the data.

SASBDB is available at https://www.sasbdb.org/.

The format of the explicit links is:

Resource abbreviation	SASBDB
Resource identifier	UniProtKB accession number

Example: Q15326

Show all entries having a cross-reference to SASBDB.

Text format

Example: Q15326

DR   SASBDB; Q15326; -.

XML format

Example: Q15326

<dbReference type="SASBDB" id="Q15326"/>

RDF format

Example: Q15326

uniprot:Q15326
  rdfs:seeAlso <http://purl.uniprot.org/sasbdb/Q15326> .
<http://purl.uniprot.org/sasbdb/Q15326>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/SASBDB> .

Changes to the controlled vocabulary of human diseases

New diseases:

• 46,XX sex reversal 5
• Agenesis of corpus callosum, cardiac, ocular, and genital syndrome
• Arrhythmogenic right ventricular dysplasia, familial, 14
• Autism 20
• Combined oxidative phosphorylation deficiency 44
• Congenital disorder of glycosylation 2T
• Deafness, autosomal dominant, 77
• Diabetes mellitus, permanent neonatal 2
• Diabetes mellitus, permanent neonatal 3
• Diabetes mellitus, permanent neonatal 4
• Epilepsy, progressive myoclonic 11
• Epileptic encephalopathy, early infantile, 86
• Epileptic encephalopathy, early infantile, 87
• Fanconi renotubular syndrome 1
• Fanconi renotubular syndrome 5
• Galactosemia 4
• Glaucoma, primary closed-angle
• Harderoporphyria
• Hao-Fountain syndrome
• Hypoparathyroidism, familial isolated, 2
• Imerslund-Grasbeck syndrome 2
• Intellectual developmental disorder with autistic features and language delay, with or without seizures
• Leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome
• Leukoencephalopathy, motor delay, spasticity, and dysarthria syndrome
• Liberfarb syndrome
• Lissencephaly 10
• Microcephaly, developmental delay, and brittle hair syndrome
• Neurodegeneration, childhood-onset, with ataxia, tremor, optic atrophy, and cognitive decline
• Neurodevelopmental, jaw, eye, and digital syndrome
• Neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity
• Neurodevelopmental disorder with hypotonia, microcephaly, and seizures
• Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures
• Neurodevelopmental disorder with language impairment and behavioral abnormalities
• Neurodevelopmental disorder with or without autistic features and/or structural brain abnormalities
• Nizon-Isidor syndrome
• Periventricular nodular heterotopia 9
• Proteinuria, chronic benign
• Pseudo-TORCH syndrome 3
• Pyrin-associated autoinflammatory disease
• Radioulnar synostosis, non-syndromic
• Seizures, early-onset, with neurodegeneration and brain calcification
• Silver-Russell syndrome 4
• Silver-Russell syndrome 5
• Skeletal dysplasia, mild, with joint laxity and advanced bone age
• Sorbitol dehydrogenase deficiency with peripheral neuropathy
• Tremor, hereditary essential 6

Modified diseases:

• Abnormal thyroid hormone metabolism -> Thyroid hormone metabolism, abnormal
• Autoinflammation, antibody deficiency, and immune dysregulation PLCG2-associated -> Autoinflammation, antibody deficiency, and immune dysregulation
• Cardiac valvular dysplasia X-linked -> Cardiac valvular dysplasia, X-linked
• Cataract 46, juvenile-onset -> Cataract 46, juvenile-onset, with or without arrhythmic cardiomyopathy
• Contractures, pterygia, and variable skeletal fusions syndrome 1A -> Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A
• Contractures, pterygia, and variable skeletal fusions syndrome 1B -> Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1B
• Cornelia de Lange syndrome 3 -> Cornelia de Lange syndrome 3 with or without midline brain defects
• Cornelia de Lange syndrome 4 -> Cornelia de Lange syndrome 4 with or without midline brain defects
• Crisponi/Cold-induced sweating syndrome 3 -> Perching syndrome
• D-lactic aciduria -> D-lactic aciduria with gout
• Deafness, X-linked, 5 -> Deafness, X-linked, 5, with peripheral neuropathy
• Diabetes mellitus, permanent neonatal -> Diabetes mellitus, permanent neonatal 1
• Dyskinesia, seizures, and intellectual developmental disorder -> Neurodevelopmental disorder with hypotonia, impaired expressive language, and with or without seizures
• Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy -> Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy 1
• Epimerase-deficiency galactosemia -> Galactosemia 3
• Familial adenomatous polyposis -> Familial adenomatous polyposis 1
• Familial hibernian fever -> Periodic fever, familial, autosomal dominant
• Familial hypercholesterolemia -> Hypercholesterolemia, familial, 1
• Familial ligand-defective apolipoprotein B-100 -> Hypercholesterolemia, familial, 2
• Galactosemia -> Galactosemia 1
• Galactosemia II -> Galactosemia 2
• Glycosylphosphatidylinositol biosynthesis defect 21 -> Neurodevelopmental disorder with brain anomalies, seizures, and scoliosis
• Glycosylphosphatidylinositol deficiency -> Glycosylphosphatidylinositol biosynthesis defect 1
• Growth restriction, severe, with distinctive facies -> Silver-Russell syndrome 3
• Hereditary desmoid disease -> Desmoid disease, hereditary
• High density lipoprotein deficiency 1 -> Tangier disease
• High density lipoprotein deficiency 2 -> Hypoalphalipoproteinemia, primary, 1
• Hypercholesterolemia, autosomal dominant, 3 -> Hypercholesterolemia, familial, 3
• Hypercholesterolemia, autosomal recessive -> Hypercholesterolemia, familial, 4
• Hypoparathyroidism, familial isolated -> Hypoparathyroidism, familial isolated, 1
• Immunodeficiency 57 -> Immunodeficiency 57 with autoinflammation
• Intellectual developmental disorder with gastrointestinal difficulties and high pain threshold -> Jansen-de Vries syndrome
• IRAK4 deficiency -> Immunodeficiency 67
• Keratitis-ichthyosis-deafness syndrome -> Keratitis-ichthyosis-deafness syndrome, autosomal dominant
• Knuckle pads, leukonychia, and sensorineural deafness -> Bart-Pumphrey syndrome
• Lujan-Fryns syndrome -> Intellectual developmental disorder, X-linked, syndromic, Lujan-Fryns type
• Melorheostosis -> Melorheostosis, isolated
• Mental retardation, autosomal dominant 9 -> NESCAV syndrome
• Mental retardation, autosomal dominant 24 -> Vulto-van Silfout-de Vries syndrome
• Mental retardation, autosomal dominant 25 -> Xia-Gibbs syndrome
• Mental retardation, autosomal dominant 27 -> Coffin-Siris syndrome 9
• Mental retardation, autosomal dominant 32 -> Arboleda-Tham syndrome
• Mental retardation, autosomal dominant 44 -> Intellectual developmental disorder, autosomal dominant 44, with microcephaly
• Mental retardation, autosomal dominant 49 -> Clark-Baraitser syndrome
• Mental retardation, X-linked, syndromic, ZDHHC9-related -> Intellectual developmental disorder, X-linked, syndromic, Raymond type
• Mental retardation, X-linked 102 -> Intellectual developmental disorder, X-linked, syndromic, Snijders Blok type
• Microcephaly, seizures, spasticity, and brain calcifications -> Diencephalic-mesencephalic junction dysplasia syndrome 1
• MYD88 deficiency -> Immunodeficiency 68
• Myopathy, proximal, and ophthalmoplegia -> Myopathy, proximal, with ophthalmoplegia
• Nail disorder, non-syndromic congenital, 10 -> Nail disorder, non-syndromic congenital, 1
• Neurodevelopmental disorder, X-linked, with craniofacial abnormalities -> Mullegama-Klein-Martinez syndrome
• Neurodevelopmental disorder with macrocephaly and with or without seizures -> Intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures
• Neuropathy, hereditary motor and sensory, 6B -> Neuropathy, hereditary motor and sensory, 6B, with optic atrophy
• Recessive hereditary megaloblastic anemia 1 -> Imerslund-Grasbeck syndrome 1
• Robinow syndrome autosomal recessive -> Robinow syndrome, autosomal recessive 1
• Rothmund-Thomson syndrome -> Rothmund-Thomson syndrome 2
• Silver-Russell syndrome -> Silver-Russell syndrome 1
• Spastic paraplegia 30, autosomal recessive -> Spastic paraplegia 30
• Thrombotic thrombocytopenic purpura congenital -> Thrombotic thrombocytopenic purpura, hereditary

Deleted diseases

• Arthrogryposis, distal, 8
• Ectodermal dysplasia, anhidrotic, with immunodeficiency, osteopetrosis and lymphedema
• Immunodeficiency, NEMO-related, without anhidrotic ectodermal dysplasia
• Recurrent isolated invasive pneumococcal disease 1
• Recurrent isolated invasive pneumococcal disease 2

Changes to the controlled vocabulary for PTMs

New terms for the feature key 'Glycosylation' ('CARBOHYD' in the flat file):

• O-alpha-linked (GlcNAc) threonine
• O-linked (Glc) threonine

Changes to keywords

New keyword:

• Carboxysome

Headline

Inflammation: the Good, the Bad and the Ugly

In a world filled with (microbial) foes, inflammation is our best friend, helping us fight against invading microorganisms, promoting wound healing and tissue regeneration. When it gets out of hand, however, it becomes our worst enemy. For instance, inflammation is required for mice to fight Influenza virus A (IAV) infections, but animals challenged with high doses of virus experience elevated levels of inflammation, destruction of airway epithelia and eventually die, unless they are deficient in MLKL protein, an endogenous protein that induces cell death in response to orthomyxovirus infection.

The mechanism leading to this fatal issue has been recently elucidated. When IAV infects cells and replicates, newly formed IAV RNA duplexes can adopt the Z-confirmation. These very peculiar RNAs are recognized by ZBP1 protein as a pathogen-associated molecular pattern (PAMP) and initiate a cascade of reactions. Activated ZBP1 recruits RIPK3, which in turn can induce one of two forms of programmed cell death, apoptosis and pro-inflammatory necroptosis. In the presence of RIPK1, apoptosis is favored. In the absence of RIPK1, RIPK3 phosphorylates MLKL, which then induces necroptosis. Programmed cell death is an effective mechanism of IAV clearance that not only eliminates infected cells to limit virus spread but also serves to catalyze adaptive immune responses. When cell death is unrestrained, or when the mode of cell death is primarily necrotic, then injury and severe illness ensue, despite virus clearance.

The dark side of inflammation also includes chronic inflammatory diseases and although progress has been made in this field, the causes that initiate pathogenic inflammatory responses still remain elusive. Could ZBP1 be a player in this deadly game? In other words, can ZBP1 be activated in the absence of any viral infections? An answer to these questions came from a recent publication by Jiao et al.. The authors showed that endogenous retroelements (EREs) produce double-stranded RNAs (dsRNAs) adopting a Z-confirmation. These dsRNAs are recognized by ZBP1 and activate it. EREs derive either from ancient retroviral infections or from active retrotransposons and constitute over half of the human and mouse genomes. Most dsRNAs identified by Jiao et al. originate from B2 and Alu short interspersed nuclear elements, followed by long interspersed nuclear elements (specifically, L1 elements) and long terminal repeat elements. Hence, these old mates of ours may still be able to mimic viral infections. Indeed in RIPK1 knockout mice, deregulation of ERE expression may trigger ZBP1-dependent skin inflammation. This mechanism may be relevant for the pathogenesis of inflammatory pathologies in humans, particularly in patients with variations in proteins that inhibit the ZBP1-MLKL-induced necroptotic pathway, such as RIPK1.

As of this release, ZBP1, RIPK3, and MLKL have been updated and are available in UniProtKB/Swiss-Prot.

UniProtKB news

Cross-references to GlyGen

Cross-references have been added to the GlyGen Computational and Informatics Resource for Glycoscience. GlyGen retrieves information from multiple international data sources, integrates and harmonizes this data and makes it searchable.

GlyGen is available at https://www.glygen.org.

The format of the explicit links is:

Resource abbreviation	GlyGen
Resource identifier	UniProtKB accession number
Optional information 1	Glycosylation details

Example: P07766

Show all entries having a cross-reference to GlyGen.

Text format

Example: P14210

DR   GlyGen; P14210; 5 sites, 8 N-linked glycans (4 sites), 1 O-linked glycan (1 site).

XML format

Example: P14210

<dbReference type="GlyGen" id="P14210">
  <property type="glycosylation" value="5 sites, 8 N-linked glycans (4 sites), 1 O-linked glycan (1 site)"/>
</dbReference>

RDF format

Example: P14210

uniprot:P07766
  rdfs:seeAlso <http://purl.uniprot.org/glygen/P14210> .
<http://purl.uniprot.org/glygen/P14210>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/GlyGen> ;
  rdfs:comment "5 sites, 8 N-linked glycans (4 sites), 1 O-linked glycan (1 site)" .

Cross-references to PathwayCommons

Cross-references have been added to the PathwayCommons, a resource that aims to collect and disseminate biological pathway and interaction data. Data is collected from partner databases and is represented in the BioPAX standard. By representing data in BioPAX, Pathway Commons is able to provide a detailed representation of a variety of biological concepts including: Biochemical reactions; gene regulatory networks; and genetic interactions; transport and catalysis events; and physical interactions involving proteins, DNA, RNA and small molecules and complexes.

PathwayCommons is available at http://www.pathwaycommons.org.

The format of the explicit links is:

Resource abbreviation	PathwayCommons
Resource identifier	UniProtKB accession number

Example: P01042

Show all entries having a cross-reference to PathwayCommons.

Text format

Example: P01042

DR   PathwayCommons; P01042; -.

XML format

Example: P01042

<dbReference type="PathwayCommons" id="P01042"/>

RDF format

Example: P01042

uniprot:P01042
  rdfs:seeAlso <http://purl.uniprot.org/pathwaycommons/P01042> .
<http://purl.uniprot.org/pathwaycommons/P01042>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/PathwayCommons> .

Change to the cross-references to GlyConnect

We have introduced an additional field in the cross-references to the GlyConnect protein glycosylation database, a platform integrating sources of information to help characterize the molecular components of protein glycosylation. This allows us to provide some additional information, e.g. about the nature of the glycans and the number of glycosylation sites.

The format of the explicit links is:

Resource abbreviation	GlyConnect
Resource identifier	Resource identifier
Optional information 1	Glycosylation details

Text format

Example: P12763

Previous format:

DR   GlyConnect; 22; -.

New format:

DR   GlyConnect; 22; 49 N-Linked glycans (3 sites), 13 O-Linked glycans (6 sites).

XML format

Example: P12763

Previous format:

<dbReference type="GlyConnect" id="22"/>

New format:

<dbReference type="GlyConnect" id="22">
  <property type="glycosylation" value="49 N-Linked glycans (3 sites), 13 O-Linked glycans (6 sites)"/>
</dbReference>

This change does not affect the XSD, but may nevertheless require code changes.

RDF format

Example: P12763

Previous format

uniprot:P12763
  rdfs:seeAlso <http://purl.uniprot.org/glyconnect/22> .
<http://purl.uniprot.org/glyconnect/22>
  rdf:type <http://purl.uniprot.org/core/Resource> ;
  <http://purl.uniprot.org/core/database> <http://purl.uniprot.org/database/GlyConnect> .

New format:

uniprot:P12763
  rdfs:seeAlso <http://purl.uniprot.org/glyconnect/22> .
<http://purl.uniprot.org/glyconnect/22>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/GlyConnect> ;
  rdfs:comment "49 N-Linked glycans (3 sites), 13 O-Linked glycans (6 sites)" .

New automatic annotation system ARBA (Association-Rule-Based Annotator)

In the UniProt Automatic Annotation pipeline which enhances unreviewed (UniProtKB/TrEMBL) records by enriching them with automatic classification and annotation, the SAAS (Statistical Automatic Annotation System) component has been superseded by the more powerful ARBA (Association-Rule-Based Annotator). ARBA is a multiclass learning system trained on expertly annotated entries in UniProtKB/Swiss-Prot. ARBA uses rule mining techniques to generate concise annotation models with the highest representativeness and coverage for annotation, based on the properties of InterPro group membership and taxonomy. ARBA employs a data exclusion set that censors data not suitable for computational annotation (such as specific biophysical or chemical properties) and generates human-readable rules for each release. ARBA rules can be browsed and searched via the website.

Changes to the controlled vocabulary of human diseases

New diseases:

• 46,XY sex reversal 11
• Al-Gazali syndrome
• Alopecia-mental retardation syndrome 4
• Anauxetic dysplasia 3
• Autoinflammation with episodic fever and lymphadenopathy
• Bone marrow failure syndrome 6
• Combined oxidative phosphorylation deficiency 40
• Combined oxidative phosphorylation deficiency 41
• Combined oxidative phosphorylation deficiency 42
• Combined oxidative phosphorylation deficiency 43
• Cone-rod dystrophy 14
• Congenital disorder of glycosylation 2R
• Diets-Jongmans syndrome
• Epilepsy, early-onset, with or without developmental delay
• Epileptic encephalopathy, early infantile, 85, with or without midline brain defects
• Genitourinary and/or brain malformation syndrome
• Holoprosencephaly 13, X-linked
• Hypervalinemia and hyperleucine-isoleucinemia
• Hypogonadotropic hypogonadism 25 with anosmia
• Immunodeficiency 66
• Intellectual developmental disorder with poor growth and with or without seizures or ataxia
• Mitochondrial DNA depletion syndrome 18
• Muscular dystrophy, limb-girdle, autosomal recessive 26
• Myopathy, congenital, with respiratory insufficiency and bone fractures
• Myopathy, congenital proximal, with minicore lesions
• Nabais Sa-de Vries syndrome 1
• Nabais Sa-de Vries syndrome 2
• Pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal
• Respiratory papillomatosis, juvenile recurrent, congenital
• Retinal dystrophy with leukodystrophy
• Rhizomelic limb shortening with dysmorphic features
• Sandestig-Stefanova syndrome
• Spinocerebellar ataxia, autosomal recessive, 28
• T-cell immunodeficiency with thymic aplasia
• T-cell lymphopenia, infantile, with or without nail dystrophy, autosomal dominant
• Triokinase and FMN cyclase deficiency syndrome
• Vertebral, cardiac, renal, and limb defects syndrome 3
• Wieacker-Wolff syndrome, female-restricted

Changes to the controlled vocabulary for PTMs

New term for the feature key 'Cross-link' ('CROSSLNK' in the flat file):

• Isoaspartyl glycine isopeptide (Gly-Asp)

New terms for the feature key 'Modified residue' ('MOD_RES' in the flat file):

• 2-oxo-5,5-dimethylhexanoate
• 3-methylisoleucine
• 3-methylvaline
• 3-methyl-D-valine
• N4-methyl-D-asparagine
• 3-hydroxyvaline (Thr)
• (3S)-3-methylglutamine
• 3-hydroxy-D-valine
• (3R)-N4-methyl-3-hydroxy-D-asparagine
• 3,3-dimethylmethionine
• Diphosphoserine
• Diphosphothreonine

Modified terms for the feature key 'Modified residue' ('MOD_RES' in the flat file):

• Lactic acid -> D-lactate
• 3-hydroxyvaline -> 3-hydroxyvaline (Val)

Headline

Mitochondrial call for help

Life is a continuous chain of issues that have to be addressed for survival and our cells know all about that. Hypoxia, amino acid deprivation, glucose deprivation, viral infection, endoplasmic reticulum stress are but a few examples. That's why eukaryotic cells have developed an elaborate signaling pathway, called the integrated stress response (ISR), which is activated in the cytosol in response to a range of physiological changes and pathological conditions. Stress stimuli that activate ISR all converge on the phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (EIF2A). Depending upon the stress stimulus, the reaction is catalyzed by one of the four following kinases: GCN2/EIF2AK4, PERK/EIF2AK3, PKR/EIF2AK2 and HRI/EIF2AK1. EIF2A phosphorylation leads to attenuation in 5' cap-dependent protein synthesis, while promoting the translation of selected mRNAs that harbor a short upstream open reading frame in their 5'-untranslated region, including those for transcription factors ATF4, ATF5 or DDIT3 (also known as CHOP). ISR is primarily a survival program, but exposure to severe stress can also lead to apoptosis.

Mitochondrial stress also strongly induces the expression of ATF4 and DDIT3, and hence triggers ISR, but the pathway signaling mitochondrial stress to the cytosol was elusive until the publication of two articles in March of this year. DDIT3 induction requires at least two mitochondrial proteins: OMA1 and DELE1, and the cytosolic kinase HRI. OMA1 is a metalloprotease located in the mitochondrial inner membrane. It is activated by mitochondrial dysfunction, possibly via membrane depolarization. OMA1 cleaves DELE1 in the intermembrane space and the N-terminally truncated DELE1 fragment enters the cytosol where it interacts with and activates HRI and hence stress response. The consequences of ISR during mitochondrial dysfunction are not yet fully understood and DELE1 may not be the only mitochondrial ISR activator, but one missing link between mitochondrial stress and ISR has been clearly established.

As of this release, the OMA1 protease and DELE1 have been updated and are available in UniProtKB/Swiss-Prot. To annotate DELE1, we took advantage of the new format announced last December, which allows us to describe product-specific features, be it that of an alternative splicing isoform, for example, or of a peptide resulting from proteolytic cleavage. EIF2AK1 activation is a function restricted to the DELE1 cleavage product, and this uniqueness is clearly reported in the 'FUNCTION' subsection dedicated to DELE1 short form.

UniProtKB news

Cross-references to IDEAL

Cross-references have been added to the IDEAL database, a database of Intrinsically Disordered proteins.

IDEAL is available at http://idp1.force.cs.is.nagoya-u.ac.jp/IDEAL/.

The format of the explicit links is:

Resource abbreviation	IDEAL
Resource identifier	Resource identifier

Example: O15162

Show all entries having a cross-reference to IDEAL.

Text format

Example: O15162

DR   IDEAL; IID00006; -.

XML format

Example: O15162

<dbReference type="IDEAL" id="IID00006"/>

RDF format

Example: O15162

uniprot:O15162
  rdfs:seeAlso <http://identifiers.org/ideal/IID00006> .
<http://identifiers.org/ideal/IID00006>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/IDEAL> .

Cross-references to BioGRID-ORCS

Cross-references have been added to the BioGRID-ORCS database, a database of CRISPR phenotype screens.

BioGRID-ORCS is available at https://orcs.thebiogrid.org.

The format of the explicit links is:

Resource abbreviation	BioGRID-ORCS
Resource identifier	Resource identifier
Optional information 1	Number of hits

Example: Q96A29

Show all entries having a cross-reference to BioGRID-ORCS.

Text format

Example: Q96A29

DR   BioGRID-ORCS; 55343; 19 Hits in 787 CRISPR Screens.

XML format

Example: Q96A29

<dbReference type="BioGRID-ORCS" id="55343">
  <property type="hits" value="19 Hits in 787 CRISPR Screens"/>
</dbReference>

RDF format

Example: Q96A29

uniprot:Q96A29
  rdfs:seeAlso <http://purl.uniprot.org/biogrid-orcs/55343> .
<http://purl.uniprot.org/biogrid-orcs/55343>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/BioGRID-ORCS> ;
  rdfs:comment "19 Hits in 787 CRISPR Screens" .

Change to the cross-references to ABCD

We have introduced an additional field in the cross-references to the ABCD (AntiBodies Chemically Defined) database, a manually curated depository of sequenced antibodies. This allows us to specify the number of sequenced antibodies available for a given protein in UniProtKB.

Text format

Example: O75084

Previous format:

DR   ABCD; O75084; -.

New format:

DR   ABCD; O75084; 10 sequenced antibodies.

XML format

Example: O75084

Previous format:

<dbReference type="ABCD" id="O75084"/>

New format:

<dbReference type="ABCD" id="O75084"/>
  <property type="antibodies" value="10 sequenced antibodies"/>
</dbReference>

This change does not affect the XSD, but may nevertheless require code changes.

RDF format

Example: O75084

Previous format:

uniprot:O75084
  rdfs:seeAlso <http://purl.uniprot.org/abcd/O75084> .
<http://purl.uniprot.org/abcd/O75084>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/ABCD> .

New format:

uniprot:O75084
  rdfs:seeAlso <http://purl.uniprot.org/abcd/O75084> .
<http://purl.uniprot.org/abcd/O75084>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/ABCD> ;
  rdfs:comment "10 sequenced antibodies" .

Change of the cross-references to MycoCLAP

The MycoCLAP resource has changed its name to CLAE and we have updated our cross-references to reflect this name change.

Cross-references to BioGRID

The BioGrid database was renamed BioGRID. We changed the database name in the relevant cross-references (DR lines in the flat file) accordingly.

Example:

DR   BioGRID; 198188; 12.

Cross-references to Unimod in the ptmlist.txt document file

The ptmlist.txt document, which is available by FTP and on the website, describes post-translational modifications (PTMs) annotated in the UniProt knowledgebase. This release sees the addition of optional cross-references from ptmlist.txt to Unimod, an open access database of protein modifications for use in mass spectrometry applications which provides molecular-level details of PTMs (both natural and non-natural) including molecular formula, target residues, monoisotopic and average mass shifts and literature references with a community-driven curation.

Example:

ID   (3R)-3-hydroxyasparagine
AC   PTM-0369
FT   MOD_RES
..
KW   Hydroxylation.
..
DR   Unimod; 35.

This new mapping to Unimod will facilitate the integration of data on PTMs identified by mass spectrometry based proteomics.

We have currently mapped 236 of the most common PTMs in UniProtKB to Unimod and will continue to add new cross-references to Unimod in forthcoming releases. This mapping of PTMs to Unimod is part of our ongoing work on the standardization of knowledge of PTMs in UniProtKB by providing cross-references to a resource which is widely used in proteomics bioinformatics. We welcome your feedback on these current and future developments.

Changes to the controlled vocabulary of human diseases

New diseases:

• Amelia, posterior, with pelvic and pulmonary hypoplasia syndrome
• Aneurysm, intracranial berry, 12
• Arthrogryposis multiplex congenita, neurogenic, with agenesis of the corpus callosum
• Basal ganglia calcification, idiopathic, 8, autosomal recessive
• Beck-Fahrner syndrome
• Bladder dysfunction, autonomic, with impaired pupillary reflex and secondary CAKUT
• CATIFA syndrome
• CEBALID syndrome
• Cerebellar hypoplasia/atrophy, epilepsy, and global developmental delay
• Ciliary dyskinesia, primary, 44
• Ciliary dyskinesia, primary, 45
• Coffin-Siris syndrome 11
• Congenital heart defects, multiple types, 7
• Corneal dystrophy, Meesmann 2
• Deafness, autosomal dominant, 7
• Deafness, autosomal dominant, 75
• Deafness, autosomal dominant, 76
• Ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomalies
• Epileptic encephalopathy, early infantile, 83
• Epileptic encephalopathy, early infantile, 84
• Heyn-Sproul-Jackson syndrome
• Hydrocephalus, normal pressure, 1
• Hypotrichosis 5
• Imagawa-Matsumoto syndrome
• Intellectual developmental disorder, autosomal dominant 63, with macrocephaly
• Intellectual developmental disorder, X-linked, syndromic, Hackman-Di Donato type
• Intellectual developmental disorder 61
• Intellectual developmental disorder 62
• Intellectual developmental disorder with hypotonia and behavioral abnormalities
• Joubert syndrome 36
• Juvenile arthritis
• Keratitis-ichthyosis-deafness syndrome, autosomal recessive
• Liang-Wang syndrome
• Long QT syndrome 16
• Lymphatic malformation 8
• Mitochondrial complex I deficiency, nuclear type 34
• Mitochondrial complex III deficiency, nuclear 10
• Myopia 27
• Neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies
• Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy
• Neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation
• Neurodevelopmental disorder with hypotonia and autistic features with or without hyperkinetic movements
• Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity
• Neuromuscular disease and ocular or auditory anomalies with or without seizures
• Neutropenia, severe congenital 8, autosomal dominant
• Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures
• Poirier-Bienvenu neurodevelopmental syndrome
• Retinitis pigmentosa 88
• Spastic paraplegia 81, autosomal recessive
• Spastic paraplegia 82, autosomal recessive
• Spermatogenic failure 1
• Spermatogenic failure 42
• Spermatogenic failure 43
• Spondyloepimetaphyseal dysplasia, Isidor-Toutain type
• Structural brain anomalies with impaired intellectual development and craniosynostosis
• Ventricular tachycardia, catecholaminergic polymorphic, 6

Modified diseases:

• Corneal dystrophy, Meesmann -> Corneal dystrophy, Meesmann 1
• Sitosterolemia -> Sitosterolemia 1

Changes to the controlled vocabulary for PTMs

New term for the feature key 'Lipidation' ('LIPID' in the flat file):

• 3'-prenyl-2',N2-cyclotryptophan

Headline

Genome integrity maintenance by HMCES

Apurinic or apyrimidinic sites, also known as abasic or AP sites, are one of the most common DNA lesions. They occur at a frequency of about 15,000 per day in human cells. In double-stranded DNA, the majority of AP sites are removed by base excision repair. After removal of the lesion, the undamaged strand is used as a template for repair synthesis. AP sites also form in single-stranded DNA (ssDNA), but until recently there was no known mechanism involved in their repair in this context. A major breakthrough in the field was reported last year in Cell.

Mohni et al. were interested in HMCES. HMCES full name is 'stem cell-specific 5-hydroxymethylcytosine-binding protein'. It was originally thought to be a regulator of 5-hydroxymethylcytosine. However, it had also been identified in the replisome, a large protein machine that carries out DNA replication. HMCES is conserved in almost all organisms, even in those that do not utilize methylcytosine for epigenetic control. Taken together, these observations suggested that HMCES could bear another crucial function, possibly in replication. Surprisingly HMCES knockout in cells did not affect DNA replication, nor cell division, but rather exacerbated cell sensitivity toward several DNA-damaging agents. Knockout cells accumulated DNA damage and exhibited increased genetic instability. Different DNA-damaging agents were tested and the only common kind of lesion they induced was the formation of AP sites.

HMCES appears to act as the initiating step of a replication-coupled repair mechanism for abasic sites in ssDNA. In eukaryotic cells, HMCES interacts with proliferating cell nuclear antigen (PCNA), an essential factor for replication, and travels with replication forks. When it senses AP sites in ssDNA, it covalently crosslinks to ssDNA AP sites generating a DNA-protein intermediate. The nature of this crosslink has been identified by crystallographic studies as a stable thiazolidine DNA-protein linkage formed between the N-terminal cysteine and the aldehyde form of the AP deoxyribose. The crosslink is so stable that its resolution requires HMCES degradation via the proteasome. This sequence of events may appear counterintuitive. It is almost as if HMCES takes a bad situation and makes it worse. However, this crosslink effectively shields the lesion from endonucleases and error-prone trans-lesion bypass (TLS) polymerases, such as REV1 and REV3L, and prevents mutagenesis they might engender. The DNA repair mechanism acting downstream of HMCES is not known.

As of this release, human HMCES, as well as YedK, an Escherichia coli homolog have been updated and are available in UniProtKB/Swiss-Prot. The exact structure of the chemical crosslink was submitted to ChEBI where more details are provided.

UniProtKB news

Change of annotation topic 'Interaction'

The annotation topic 'Interaction' provides information about binary protein-protein interactions. This data is curated in the IntAct database and a quality-filtered subset is imported into UniProtKB at each release.

In the context of improving the functional annotation of different gene products in UniProtKB/Swiss-Prot, we have started to import more detailed data from IntAct. Our previous representation of a binary protein-protein interaction provided details only for the protein that was described in another entry. This left ambiguity in UniProtKB/Swiss-Prot entries that describe more than one protein (isoforms or/and products of proteolytic cleavage). To address this we now describe both interacting proteins by unique UniProtKB identifiers.

This change affects the three main UniProtKB distribution formats (text, XML, RDF). The details are described for each format in a separate section below. The following placeholders are used in the format descriptions:

• <Interactant> represents a UniProtKB protein.
  • <Accession> is a UniProtKB accession number.
  • <IsoId> is a UniProtKB isoform ID.
  • <ProductId> is a UniProtKB product ID.
  • <Gene> is either the gene name, ordered locus name or ORF name of the gene that encodes the UniProtKB protein (see Gene names).

• <Experiments> is the number of experiments in IntAct that support an interaction.

• <IntActId> is an IntAct protein ID.

Note: The format descriptions make use of POSIX ERE syntax.

Text format

Previous format:

CC   -!- INTERACTION:
CC       <Interactant>( \(xeno\))?; NbExp=<Experiments>; IntAct=<IntActId>, <IntActId>;
CC       <Interactant>( \(xeno\))?; NbExp=<Experiments>; IntAct=<IntActId>, <IntActId>;
CC       ...

The <Interactant> was described in the following way:

Self|(<Accession>|<IsoId>):(<Gene>|-)

Where Self represents a self-interaction and a dash is shown for proteins with an undefined <Gene>. xeno is an optional flag that indicates that the interacting proteins are derived from different species. This may be due to the experimental set-up or may reflect a pathogen-host interaction.

New format:

CC   -!- INTERACTION:
CC       <Interactant>; <Interactant>;( Xeno;)? NbExp=<Experiments>; IntAct=<IntActId>, <IntActId>;
CC       <Interactant>; <Interactant>;( Xeno;)? NbExp=<Experiments>; IntAct=<IntActId>, <IntActId>;
CC       ...

Where

• the first <Interactant> is represented by:

  (<Accession>|<IsoId>|<ProductId>)
  

• the second <Interactant> is represented by:

  (<Accession>|<IsoId>|<ProductId> [<Accession>])(: <Gene>)?
  

Example: P11309

Binary interactions with different isoforms that are described in P11309.

Previous format:

CC   -!- INTERACTION:
CC       Q9BZS1-1:FOXP3; NbExp=3; IntAct=EBI-1018629, EBI-9695448;
CC       Q9UNQ0:ABCG2; NbExp=5; IntAct=EBI-1018633, EBI-1569435;

New format:

CC   -!- INTERACTION:
CC       P11309-1; Q9BZS1-1: FOXP3; NbExp=3; IntAct=EBI-1018629, EBI-9695448;
CC       P11309-2; Q9UNQ0: ABCG2; NbExp=5; IntAct=EBI-1018633, EBI-1569435;

Example: P27958 and Q9NPY3

Binary interaction with a product of proteolytic cleavage. Interactions involving products of proteolytic cleavage were previously not imported from IntAct, therefore only the new data/format is shown.

New data and format of P27958:

CC   -!- INTERACTION:
CC       PRO_0000037566; Q9NPY3: CD93; Xeno; NbExp=2; IntAct=EBI-6377335, EBI-1755002;

New data and format of Q9NPY3:

CC   -!- INTERACTION:
CC       Q9NPY3; PRO_0000037566 [P27958]; Xeno; NbExp=2; IntAct=EBI-1755002, EBI-6377335;

XML format

The UniProtKB XSD represents a binary interaction with:

• two interactant elements of interactantType

• a boolean organismsDiffer element that indicates that the interacting proteins are derived from different species. This may be due to the experimental set-up or may reflect a pathogen-host interaction.

• an experiments element that gives the number of experiments in IntAct that support an interaction.

The interactantType uses an interactantGroup to represent a sequence of:

• an id element

• an optional label element

We have added an optional dbReference element to the interactantGroup to allow us to represent the UniProtKB <Accession> for a <ProductId>:

<xs:group name="interactantGroup">
        <xs:sequence>
            <xs:element name="id" type="xs:string"/>
            <xs:element name="label" type="xs:string" minOccurs="0"/>
            <xs:element name="dbReference" type="dbReferenceType" minOccurs="0"/>
        </xs:sequence>
    </xs:group>

Previous format:

<comment type="interaction">
  <interactant intactId="<IntActId>"/>
  <interactant intactId="<IntActId>">
    <id><Accession>|<IsoId></id>
    <label><Gene></label>
  </interactant>
  <organismsDiffer>true|false</organismsDiffer>
  <experiments><Experiments></experiments>
</comment>

New format:

<comment type="interaction">
  <interactant intactId="<IntActId>">
    <id><Accession>|<IsoId>|<ProductId></id>
  </interactant>
  <interactant intactId="<IntActId>">
    <id><Accession>|<IsoId>|<ProductId></id>
    <label><Gene></label>
    <!-- If <id> is a <ProductId>: -->
    <dbReference type="UniProtKB" id="<Accession>"/>
  </interactant>
  <organismsDiffer>true|false</organismsDiffer>
  <experiments><Experiments></experiments>
</comment>

Example: P11309

Binary interactions with different isoforms that are described in P11309.

Previous format:

<comment type="interaction">
  <interactant intactId="EBI-1018629"/>
  <interactant intactId="EBI-9695448">
    <id>Q9BZS1-1</id>
    <label>FOXP3</label>
  </interactant>
  <organismsDiffer>false</organismsDiffer>
  <experiments>3</experiments>
</comment>
<comment type="interaction">
  <interactant intactId="EBI-1018633"/>
  <interactant intactId="EBI-1569435">
    <id>Q9UNQ0</id>
    <label>ABCG2</label>
  </interactant>
  <organismsDiffer>false</organismsDiffer>
  <experiments>5</experiments>
</comment>

New format:

<comment type="interaction">
  <interactant intactId="EBI-1018629">
    <id>P11309-1</id>
  </interactant>
  <interactant intactId="EBI-9695448">
    <id>Q9BZS1-1</id>
    <label>FOXP3</label>
  </interactant>
  <organismsDiffer>false</organismsDiffer>
  <experiments>3</experiments>
</comment>
<comment type="interaction">
  <interactant intactId="EBI-1018633">
    <id>P11309-2</id>
  </interactant>
  <interactant intactId="EBI-1569435">
    <id>Q9UNQ0</id>
    <label>ABCG2</label>
  </interactant>
  <organismsDiffer>false</organismsDiffer>
  <experiments>5</experiments>
</comment>

Example: P27958 and Q9NPY3

Binary interaction with a product of proteolytic cleavage. Interactions involving products of proteolytic cleavage had previously not been imported from IntAct, therefore only the new data/format is shown.

New data and format of P27958:

<comment type="interaction">
  <interactant intactId="EBI-6377335">
    <id>PRO_0000037566</id>
  </interactant>
  <interactant intactId="EBI-1755002">
    <id>Q9NPY3</id>
    <label>CD93</label>
  </interactant>
  <organismsDiffer>true</organismsDiffer>
  <experiments>2</experiments>
</comment>

New data and format of Q9NPY3:

<comment type="interaction">
  <interactant intactId="EBI-1755002">
    <id>Q9NPY3</id>
  </interactant>
  <interactant intactId="EBI-6377335">
    <id>PRO_0000037566</id>
    <dbReference type="UniProtKB" id="P27958"/>
  </interactant>
  <organismsDiffer>true</organismsDiffer>
  <experiments>2</experiments>
</comment>

RDF format

The UniProt RDF schema ontology represents a binary interaction with an interaction property whose rdfs:range is the Interaction class. This class is the domain of the following properties that describe the interaction:

• participant refers to an object of type Participant.

• xeno is a boolean that indicates that the interacting proteins are derived from different species. This may be due to the experimental set-up or may reflect a pathogen-host interaction.

• experiments gives the number of experiments in IntAct that support an interaction.

A Participant is identified by its unique IntAct identifier. It also refers to the corresponding UniProtKB protein which is represented as described in the news article about the functional annotation of different gene products in UniProtKB/Swiss-Prot. An optional rdfs:label property may provide the gene name, ordered locus name or ORF name of the gene that encodes the UniProtKB protein.

The RDF schema ontology required no changes to represent the more detailed data that we now import from IntAct. Due to the symmetry of binary interactions, the UniProt SPARQL server already provided access to the full details about both interacting proteins. We have however taken this opportunity to normalize the URI of a binary interaction so that the two UniProtKB entries that describe the interacting proteins refer to the interaction with the same URI:

Previous format:

<<Accession>#interaction-<IntActId>-<IntActId>> .

New format:

<http://purl.uniprot.org/intact/<IntActId>-<IntActId>> .

Example: P11309 and Q8N9N5

Previous format:

P11309:

<P11309#interaction-696621-744695>

Q8N9N5:

<Q8N9N5#interaction-744695-696621>

New format:

P11309 and Q8N9N5:

<http://purl.uniprot.org/intact/EBI-696621-EBI-744695>

Cross-references to Antibodypedia

Cross-references have been added to Antibodypedia, a portal providing access to publicly available research antibodies towards human protein targets from many different providers.

Antibodypedia is available at https://www.antibodypedia.com/.

The format of the explicit links is:

Resource abbreviation	Antibodypedia
Resource identifier	Resource identifier
Optional information 1	Number of antibodies

Example: P04626

Show all entries having a cross-reference to Antibodypedia.

Text format

Example: P04626

DR   Antibodypedia; 740; 5394 antibodies.

XML format

Example: P04626

<dbReference type="Antibodypedia" id="740">
   <property type="antibodies" value="5394 antibodies"/>
</dbReference>

RDF format

Example: P04626

uniprot:P04626
  rdfs:seeAlso <http://purl.uniprot.org/antibodypedia/740> .

<http://purl.uniprot.org/antibodypedia/740>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/Antibodypedia> ;
  rdfs:comment "5394 antibodies" .

Cross-references to MetOSite

Cross-references have been added to MetOSite, a database of methionine sulfoxide sites. Each collected site has been classified according to the effect of its sulfoxidation on the biological properties of the modified protein. Thus, MetOSite documents cases where the sulfoxidation of methionine leads to gain or loss of activity, increased or decreased protein-protein interaction susceptibility, and to changes in protein stability or in subcellular location.

MetOSite is available at https://metosite.uma.es/.

The format of the explicit links is:

Resource abbreviation	MetOSite
Resource identifier	UniProtKB accession number

Example: P10987

Show all entries having a cross-reference to MetOSite.

Text format

Example: P10987

DR   MetOSite; P10987; -.

XML format

Example: P10987

<dbReference type="MetOSite" id="P10987"/>

RDF format

Example: P10987

uniprot:P10987
  rdfs:seeAlso <http://purl.uniprot.org/metosite/P10987> .
<http://purl.uniprot.org/metosite/P10987>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/MetOSite> .

Cross-references to PHI-base

Cross-references have been added to PHI-base, a database providing expertly curated molecular and biological information on genes proven to affect the outcome of pathogen-host interactions.

PHI-base is available at http://www.phi-base.org/.

The format of the explicit links is:

Resource abbreviation	PHI-base
Resource identifier	Resource identifier

Example: Q00310

Show all entries having a cross-reference to PHI-base.

Text format

Example: Q00310

DR   PHI-base; PHI:104; -.

XML format

Example: Q00310

<dbReference type="PHI-base" id="PHI:104"/>

RDF format

Example: Q00310

uniprot:Q00310
  rdfs:seeAlso <http://purl.uniprot.org/phi-base/PHI:104> .
<http://purl.uniprot.org/phi-base/PHI:104>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/PHI-base> .

Change to the cross-references to Human Protein Atlas (HPA)

We have changed the way we present the Human Protein Atlas database cross-references. Links between UniProtKB entries and HPA used to be established by HPA antibody identifier, but are now based on Ensembl Gene identifiers.

We have also introduced an additional field in these cross-references to indicate the level of RNA tissue specificity. The RNA specificity category is based on mRNA expression levels in the analyzed samples. The categories include: 'Tissue enriched', 'Group enriched', 'Tissue enhanced', 'Low tissue specificity' and 'Not detected'. For more details on these categories, see the Classification of transcriptomics data by Human Protein Atlas.

Text format

Example: Q9NSG2

Previous format:

DR   HPA; HPA023778; -.
DR   HPA; HPA024451; -.

New format:

DR   HPA; ENSG00000000460; Tissue enhanced (lymphoid).

XML format

Example: Q9NSG2

Previous format:

<dbReference type="HPA" id="HPA023778"/>
<dbReference type="HPA" id="HPA024451"/>

New format:

<dbReference type="HPA" id="ENSG00000000460">
  <property type="expression patterns" value="Tissue enhanced (lymphoid)"/>
</dbReference>

This change does not affect the XSD, but may nevertheless require code changes.

RDF format

Example: Q9NSG2

Previous format:

uniprot:Q9NSG2
  rdfs:seeAlso <http://purl.uniprot.org/hpa/HPA023778> ,
               <http://purl.uniprot.org/hpa/HPA024451> .
<http://purl.uniprot.org/hpa/HPA023778>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/HPA> .
<http://purl.uniprot.org/hpa/HPA024451>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/HPA> .

New format:

uniprot:Q9NSG2
  rdfs:seeAlso <http://www.proteinatlas.org/ENSG00000000460> .
<http://www.proteinatlas.org/ENSG00000000460>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/HPA> ;
  rdfs:comment "Tissue enhanced (lymphoid)" .

Changes to the controlled vocabulary of human diseases

New diseases:

• Ciliary dyskinesia, primary, 42
• Ciliary dyskinesia, primary, 43
• Epileptic encephalopathy, early infantile, 81
• Epileptic encephalopathy, early infantile, 82
• Hemolytic anemia due to glutathione reductase deficiency
• Hydrocephalus, congenital communicating, 1
• Intellectual developmental disorder, autosomal recessive 72
• Intellectual developmental disorder with impaired language and dysmorphic facies
• Intellectual developmental disorder with short stature and behavioral abnormalities
• Intellectual developmental disorder with speech delay, autism and dysmorphic facies
• Leukodystrophy, hypomyelinating, 19, transient infantile
• Megabladder, congenital
• Megacystis-microcolon-intestinal hypoperistalsis syndrome
• Microphthalmia, syndromic, 15
• Mitochondrial complex V deficiency, nuclear type 6
• Myopathy, congenital, with structured cores and Z-line abnormalities
• Myopathy, distal, 6, adult onset, autosomal dominant
• Neurodevelopmental disorder with absent language and variable seizures
• Neurodevelopmental disorder with behavioral abnormalities, absent speech, and hypotonia
• Neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies
• Neurodevelopmental disorder with macrocephaly and with or without seizures
• Neurodevelopmental disorder with non-specific brain abnormalities and with or without seizures
• Neurodevelopmental disorder with spastic quadriplegia, optic atrophy, seizures, and structural brain anomalies
• Neuronal intranuclear inclusion disease
• Neurooculocardiogenitourinary syndrome
• Premature ovarian failure 16
• Pulmonary fibrosis, and/or bone marrow failure, telomere-related, 5
• Retinitis pigmentosa 87 with choroidal involvement
• Short stature and microcephaly with genital anomalies
• Sitosterolemia 2
• Spondyloepimetaphyseal dysplasia, X-linked, with hypomyelinating leukodystrophy
• Zimmermann-Laband syndrome 3

Modified diseases:

• 3-methylglutaconic aciduria with cataracts, neurologic involvement and neutropenia -> 3-methylglutaconic aciduria 7
• Cowchock syndrome -> Charcot-Marie-Tooth disease, X-linked recessive, 4, with or without cerebellar ataxia
• Developmental delay, intellectual disability, obesity, and dysmorphic features -> Chung-Jansen syndrome
• Developmental delay with short stature, dysmorphic features, and sparse hair -> Developmental delay with short stature, dysmorphic facial features, and sparse hair
• Ischiocoxopodopatellar syndrome -> Ischiocoxopodopatellar syndrome with or without pulmonary arterial hypertension
• Mental retardation, X-linked, syndromic, 36 -> Basilicata-Akhtar syndrome
• Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration -> Metabolic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration
• Neuropathy, hereditary motor and sensory, 6A -> Neuropathy, hereditary motor and sensory, 6A, with optic atrophy
• Seizures, scoliosis, and macrocephaly syndrome -> Seizures, scoliosis, and macrocephaly/microcephaly syndrome
• Spondyloepimetaphyseal dysplasia MATN3-related -> Spondyloepimetaphyseal dysplasia, MATN3-related
• Spondyloepimetaphyseal dysplasia Missouri type -> Spondyloepimetaphyseal dysplasia, Missouri type
• Spondyloepimetaphyseal dysplasia short limb-hand type -> Spondyloepimetaphyseal dysplasia, short limb-hand type

Changes to the controlled vocabulary for PTMs

New terms for the feature key 'Modified residue' ('MOD_RES' in the flat file):

• Thiazolidine linkage to a ring-opened DNA abasic site
• Deoxyhypusine

RDF news

Change of URIs for the Human Protein Atlas (HPA) database

For historic reasons, UniProt had to generate URIs to cross-reference databases that did not have an RDF representation. Our policy is to replace these by the URIs generated by the cross-referenced database once it starts to distribute an RDF representation of its data.

The URIs for the Human Protein Atlas database have therefore been updated from:

http://purl.uniprot.org/hpa/<ID>

to:

http://www.proteinatlas.org/<ID>

If required for backward compatibility, you will be able to use the following query to add the old URIs:

PREFIX owl:<http://www.w3.org/2002/07/owl#>
PREFIX up:<http://purl.uniprot.org/core/>
INSERT
{
   ?protein rdfs:seeAlso ?old .
   ?old owl:sameAs ?new .
   ?old up:database <http://purl.uniprot.org/database/HPA> .
}
WHERE
{
   ?protein rdfs:seeAlso ?new .
   ?new up:database <http://purl.uniprot.org/database/HPA> .
   BIND(iri(concat('http://purl.uniprot.org/hpa/', substr(str(?new),29))) AS ?old)
}

The dereferencing of existing http://purl.uniprot.org/hpa/<ID> URIs will be maintained.

Standardized MD5 checksums in UniProt RDF

The UniProt databases UniProtKB, UniRef and UniParc have historically provided a CRC-64 checksum for the amino acid sequences. In the UniParc RDF representation we had already introduced an MD5 checksum, and we have now replaced it with a SPARQL 1.1 compliant MD5 representation (lowercase string) and use this across all databases. This allows to use the MD5 function defined in SPARQL 1.1 to check that the sequence string is not corrupted, without the need to use the lowercase (LCASE) function and a cast to string, as it was formerly the case:

PREFIX rdf:<http://www.w3.org/1999/02/22-rdf-syntax-ns#>
PREFIX up:<http://purl.uniprot.org/core/>
SELECT ?computedMD5 ((?uniprotMD5 = ?computedMD5) AS ?md5SumsMatch)
WHERE
{
  ?protein a up:Protein ;
    up:sequence ?sequence .
  ?sequence rdf:value ?value ;
    up:md5Checksum ?uniprotMD5 .
  BIND(MD5(?value) AS ?computedMD5)
}

Headline

Coronavirus SARS-CoV-2 in UniProtKB

At the end of 2019, a novel coronavirus (nCoV) of animal origin started infecting humans, initiating a severe outbreak in China. nCoV infection can result in severe and even fatal respiratory diseases, such as acute respiratory distress syndrome. The virus is highly contagious and transmission occurs via airborne droplets and contact. On January 30^th, 2019-nCoV was designated a global health emergency by the WHO. On February 11^th, the WHO called the disease caused by the virus COVID-19, and the virus itself was named Severe Acute Respiratory Syndrome-related coronavirus 2 or SARS-CoV-2 by the International Committee on Taxonomy of Viruses (ICTV).

SARS-CoV-2 belongs to the large family of Coronaviridae, genus Betacoronavirus. This genus comprises mainly vertebrate respiratory viruses, including HCoV-OC43, which is responsible for 10% of common colds, and SARS, which caused an epidemic in 2003, resulting in over 8,000 infected individuals in 26 countries. The novel coronavirus genome has been sequenced. Its close similarity to SARS suggests it has emerged from the same reservoir, namely bats.

With a size of 30 kb, coronaviruses have the largest RNA genomes known to date. The genome encodes a polyprotein 1a that can be elongated by ribosomal frameshifting to produce polyprotein 1ab. The short and elongated polyproteins contain 11 and 15 chains, respectively, and are dedicated to viral RNA transcription and replication, while controlling the host antiviral defense. A strategy used by the virus to escape host cell innate immunity is to induce the formation of a specialized intracellular compartment from the endoplasmic reticulum, called endoplasmic spherules, which protects viral dsRNA replication intermediates. Later on subgenomic mRNAs are translated to produce virion structural proteins and yet another set of immune modulatory factors. Virions are assembled at the ER-Golgi intermediate compartment (or ERGIC) and exported out of the cell. The freshly exported virion is not yet infectious. Its surface is covered by spikes, giving the impression a crown (corona in Latin, hence its name), but spike proteins have to be cleaved in order to become functional and to confer infectivity on the virion. The activating proteolytic cleavages occur in the extracellular space.

It is at the level of spike proteins that SARS-CoV-2 diverges from SARS, differing in both amino acid sequence and glycosylation. The SARS-CoV-2 spike protein cleavage site comprises several arginines, making it an excellent substrate for many host proteases. This feature is predicted to enhance virus tropism and virulence. SARS-CoV-2 interacts with the same host receptor as SARS, ACE2, which presumably explains why both viruses infect lungs, as well as the small intestine and kidney. The functions of several other SARS-CoV-2 proteins are still unclear and need further investigations. Among them is SARS-CoV-2 NS8 protein, which shares sequence similarity with some Bat-hosted coronavirus NS8 proteins, but is entirely different from SARS NS8a or NS8b. Thus, in spite of many similarities to SARS and other coronaviruses, SARS-CoV-2 displays unique molecular features that lead to unpredictable behavior during infection.

SARS-CoV-2 protein sequences from the current public health emergency have been annotated in UniProtKB and made available as a pre-release dataset on the UniProt FTP site. These entries will be available in the usual file formats as part of release 2020_02.

UniProt release news

Change of release cycle

Starting with release 2020_01 of February 26th, UniProt releases are published every 8 weeks. Release 2020_02 is scheduled for April 22nd, 2020.

See also: How frequently is UniProt released? What is the synchronization delay with other databases?

UniProtKB news

Changes to the controlled vocabulary of human diseases

New diseases:

• Abdominal obesity-metabolic syndrome 4
• Cortical dysplasia, complex, with other brain malformations 10
• Diarrhea 11, malabsorptive, congenital
• Diencephalic-mesencephalic junction dysplasia syndrome 2
• Deafness, autosomal dominant, 27
• Epilepsy, familial adult myoclonic, 3
• Epilepsy, familial adult myoclonic, 4
• Immunodeficiency 65
• Infantile liver failure syndrome 3
• Intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies
• Lessel-Kubisch syndrome
• Lower urinary tract obstruction, congenital
• Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies
• Noonan syndrome 12
• Oculopharyngodistal myopathy 1
• Osteogenesis imperfecta 20
• Pancreatic cancer 5
• Pontocerebellar hypoplasia 13
• Retinitis pigmentosa 86
• Rothmund-Thomson syndrome 1
• Siddiqi syndrome
• Snijders Blok-Fisher syndrome.
• Spermatogenic failure 39
• Spermatogenic failure 40
• Spermatogenic failure 41
• Usher syndrome 1M
• Weiss-Kruszka syndrome

Deleted disease

• Popov-Chang syndrome

Changes to the controlled vocabulary for PTMs

New term for the feature key 'Modified residue' ('MOD_RES' in the flat file):

• N6-lactoyllysine

Modified term for the feature key 'Modified residue' ('MOD_RES' in the flat file):

• 6-(S-cysteinyl)-8alpha-(pros-histidyl)-FAD (Cys-His) -> 6-(S-cysteinyl)-8alpha-(pros-histidyl)-FAD (His-Cys)

Headline

Thicker than water

We know about blood types and their incompatibility; transfusing someone who is O- with AB+ blood can be lethal. The ABO alleles present on chromosome 9 decide our blood type. The A and B antigens are a set of red blood cell surface carbohydrates ending in α-1,3-linked N-acetylgalactosamine and α-1,3-linked galactose respectively, while type O blood has neither of these cell surface sugars. Sequence variations in the ABO gene determine if the encoded protein has α-1,3-N-acetylgalactosaminyltransferase activity and makes type A blood, or if it has α-1,3-galactosyltransferase activity and makes type B blood. When both alleles are present, we make type AB blood. Deletion of a single G nucleotide in the ABO gene leads to a truncated inactive product and type O blood, which has the non-modified H antigen.

To improve the usability of blood, people have tried for years to find a way to enzymatically convert A or B blood to type O; it seems an obvious way to increase the supply of universal donor (which would still require Rhesus matching). While such enzymes have been found, they are not yet ideal, as they either work at high concentration or have very specific buffer requirements, not met by blood.

By screening human fecal metagenomic libraries, Rahfeld et al. have isolated a pair of enzymes from the obligate gut anaerobe Flavonifractor plautii that efficiently converts the A to H antigen (type O). The first enzyme (A type blood N-acetyl-alpha-D-galactosamine deacetylase, ADAC) deacylates all A antigen subtypes tested (and there are many), while the second enzyme (A type blood alpha-D-galactosamine galactosaminidase, AGAL) removes the residual galactosamine moiety. This reaction can occur on red blood cells and in blood, as opposed to a buffer system, and at low enzyme concentration, and thus shows promise for uses in blood production. Further testing is underway, and we still need a way to remove the B antigen, but this could well help increase the flexibility of our blood supply. It still won’t solve the world shortage of blood, only more donors can do that...

As of this release, ADAC and AGAL have been annotated and are available in UniProtKB/Swiss-Prot.

UniProtKB news

Change of FT and CC sections in UniProtKB text format

We have changed the format of the FT and CC section of the UniProtKB text files. The changes of the FT section likely affects all parsers, and software will have to be adapted accordingly. The changes of the CC section are smaller, but may also require code adaptations depending on the CC annotation types that you parse.

The motivation for this change is described in the section "Functional annotation of different gene products in UniProtKB/Swiss-Prot" below, where you can also find the technical details and examples under the heading Text format.

Change of line length in UniProtKB text format

Historically, the lines of the UniProtKB text format have been wrapped at 75 characters for technical reasons (terminal screen size and data processing capabilities). When these technical restrictions vanished, we introduced exceptions for data like URLs, protein names and cross-references where line wrapping does not improve readability. These lines can be up to 255 characters long, but most lines are still wrapped at 75 characters for readability. We have now increased the maximum number of characters for wrapped lines to 80 in the context of the format change of the FT section of the UniProtKB text format for the functional annotation of different gene products in UniProtKB/Swiss-Prot described below.

Functional annotation of different gene products in UniProtKB/Swiss-Prot

To reduce database redundancy, the UniProtKB/Swiss-Prot policy is to describe, whenever possible, all protein products that are encoded by one gene in a given species in a single entry. This includes isoforms generated by alternative promoter usage, alternative splicing, alternative initiation and ribosomal frameshifting. We assign a name and a unique identifier to each isoform and choose one of them to be the canonical sequence that is shown in the UniProtKB text and XML format (the RDF format shows all sequences). All positional annotations in the entry referred to this canonical sequence until this release. Some gene products are precursors that are processed by proteolytic cleavage to generate the biologically active product(s). These products are described by their location on the sequence, a name and a unique identifier.

When isoforms, or products of proteolytic cleavage, are known to differ in their function or other characteristics, we generally describe this in the text of the respective annotations. To make this information also accessible to software applications, we adapted the UniProtKB text format to describe the product to which an annotation applies in a computer-processable way. The schemas of the XML and RDF format already supported this and required no changes. The following sections describe the changes for the text format and how the data is represented in the XML and RDF format.

Text format

Isoforms are described in ALTERNATIVE PRODUCTS annotations in the CC section. The products of proteolytic cleavage are described in PEPTIDE and CHAIN annotations in the FT section. All three annotation types provide a name (<ProductName>) and a unique ID (<ProductId>) for the product that they describe:

• ALTERNATIVE PRODUCTS annotations show the name of an isoform in the Name field and its ID in the IsoId field.

  CC   -!- ALTERNATIVE PRODUCTS:
  ...
  CC       Name=<ProductName>;
  CC         IsoId=<ProductId>; Sequence=Displayed;
  

• PEPTIDE and CHAIN annotations showed the name of a proteolytic cleavage product in the <Description> field and its ID in the FTId field in the previous text format:

  FT   CHAIN       <B>    <E>       <ProductName>.
  FT                                /FTId=<ProductId>.
  

  In the new text format that is described in more details in the FT section they are shown in the /note= and /id= qualifiers, respectively:

  FT   CHAIN           <B>..<E>
  FT                   /note="<ProductName>"
  FT                   /id="<ProductId>"
  

Example: O60443

CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=3;
CC       Name=1; Synonyms=Long;
CC         IsoId=O60443-1; Sequence=Displayed;
CC       Name=2; Synonyms=Short;
CC         IsoId=O60443-2; Sequence=VSP_004190;
CC         Note=No experimental confirmation available.;
CC       Name=3;
CC         IsoId=O60443-3; Sequence=VSP_044276;
...
FT   CHAIN         1    496       Gasdermin-E.
FT                                /FTId=PRO_0000148178.
FT   CHAIN         1    270       Gasdermin-E, N-terminal.
FT                                {ECO:0000269|PubMed:27281216,
FT                                ECO:0000305|PubMed:28459430}.
FT                                /FTId=PRO_0000442786.
FT   CHAIN       271    496       Gasdermin-E, C-terminal.
FT                                {ECO:0000305|PubMed:28459430}.
FT                                /FTId=PRO_0000442787.

CC section

The annotation types in the CC section describe a product by its name (isoform names are prefixed with the term "Isoform"). In the format descriptions below this name is represented by <ProductName>. Different products are described in separate annotations (see FUNCTION and BIOPHYSICOCHEMICAL PROPERTIES examples).

All annotation types of the CC section start with:

CC   -!- <TYPE>:

Where <TYPE> is a value from the controlled vocabulary of annotation types.

In some annotation types the content of the annotation used to directly follow the <TYPE>, and lines were wrapped at 75 chars:

CC   -!- <TYPE>: <Content>

In the new format a <ProductName> may be added between the <TYPE> and the <Content> and lines are wrapped at 80 chars (see Change of line length in UniProtKB text format ):

CC   -!- <TYPE>: [<ProductName>]: <Content>

The <ProductName> is surrounded by square brackets and separated by a colon from the <Content> to make it possible to parse it with a POSIX ERE like this one:

^CC   -!- ([^:]+):(?: \[(.+?)\]:)? (.+)

Where $1=<TYPE>, $2=<ProductName>, $3=<Content>.

In annotation types where the content is structured as a list of different fields that are formatted according to custom rules for better readability, the annotation content starts on a new line:

CC   -!- <TYPE>:
CC       <Content>

In the new format a <ProductName> may be added after the <TYPE> and this line is not wrapped (i.e. it may in rare cases exceed 80 chars).

CC   -!- <TYPE>: [<ProductName>]:
CC       <Content>

The format of the <Content> remains unchanged.

A <ProductName> cannot be added to ALTERNATIVE PRODUCTS and INTERACTION annotations. The INTERACTION format will be adapted in a different way to describe binary interactions that involve isoforms and/or products of proteolytic cleavage (see Change of annotation topic 'Interaction' ).

Please note that the previous text format of SUBCELLULAR LOCATION, COFACTOR and MASS SPECTROMETRY annotations already allowed to specify a product name/ID, but we have adapted it to be consistent with all other annotation types.

Representative examples for different annotation types are shown here:

FUNCTION

Example: Q96F85

CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1; Synonyms=CRIP1a;
CC         IsoId=Q96F85-1; Sequence=Displayed;
CC       Name=2; Synonyms=CRIP1b;
CC         IsoId=Q96F85-2; Sequence=VSP_035598;

Previous format:

CC   -!- FUNCTION: Isoform 1 suppresses cannabinoid receptor CNR1-mediated
CC       tonic inhibition of voltage-gated calcium channels. Isoform 2 does
CC       not have this effect. {ECO:0000269|PubMed:17895407}.

New format:

CC   -!- FUNCTION: [Isoform 1]: Suppresses cannabinoid receptor CNR1-mediated
CC       tonic inhibition of voltage-gated calcium channels.
CC       {ECO:0000269|PubMed:17895407}.
CC   -!- FUNCTION: [Isoform 2]: Does not suppress cannabinoid receptor CNR1-
CC       mediated tonic inhibition of voltage-gated calcium channels.
CC       {ECO:0000269|PubMed:17895407}.

DISEASE

Example: P35555

FT   CHAIN      2732   2871       Asprosin. {ECO:0000305|PubMed:27087445,
FT                                ECO:0000305|PubMed:9817919}.
FT                                /FTId=PRO_0000436882.

Previous format:

CC   -!- DISEASE: Marfan lipodystrophy syndrome (MFLS) [MIM:616914]: A
CC       syndrome characterized by congenital ...
CC       Note=The disease is caused by mutations affecting the gene
CC       represented in this entry. Asprosin: Mutations specifically affect
CC       Asprosin, a hormone peptide present at the C-terminus of
CC       Fibrillin-1 chain, which is cleaved from Fibrillin-1 following
CC       secretion (PubMed:27087445). {ECO:0000269|PubMed:27087445}.

New format:

CC   -!- DISEASE: [Asprosin]: Marfan lipodystrophy syndrome (MFLS) [MIM:616914]:
CC       A syndrome characterized by congenital ...
CC       Note=The disease is caused by mutations affecting the gene represented
CC       in this entry. {ECO:0000269|PubMed:27087445}.

SUBCELLULAR LOCATION

Please note that the previous text format of SUBCELLULAR LOCATION annotations already allowed to describe a product by its name in the optional first field. To be consistent with all other annotation types we have added square brackets around the product name.

Example: Q13421

CC   -!- ALTERNATIVE PRODUCTS:
...
CC       Name=3; Synonyms=SMRP;
CC         IsoId=Q13421-2; Sequence=VSP_021059, VSP_021060;
...
FT   CHAIN        37    286       Megakaryocyte-potentiating factor.
FT                                /FTId=PRO_0000253560.

Previous format:

CC   -!- SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor, GPI-anchor.
CC       Golgi apparatus.
CC   -!- SUBCELLULAR LOCATION: Megakaryocyte-potentiating factor: Secreted.
CC   -!- SUBCELLULAR LOCATION: Isoform 3: Secreted.

New format:

CC   -!- SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor, GPI-anchor. Golgi
CC       apparatus.
CC   -!- SUBCELLULAR LOCATION: [Megakaryocyte-potentiating factor]: Secreted.
CC   -!- SUBCELLULAR LOCATION: [Isoform 3]: Secreted.

MASS SPECTROMETRY

Please note that the previous text format of MASS SPECTROMETRY annotations already allowed to describe a product (by its sequence range and an optional isoform ID) in the Range field. To be consistent with all other annotation types we have replaced the Range field by a <ProductName> field.

Example: P09493

CC   -!- ALTERNATIVE PRODUCTS:
...
CC       Name=3; Synonyms=Fibroblast, TM3;
CC         IsoId=P09493-3; Sequence=VSP_006577, VSP_006579;

Previous format:

CC   -!- MASS SPECTROMETRY: Mass=32875.93; Method=MALDI; Range=1-284
CC       (P09493-3); Evidence={ECO:0000269|PubMed:11840567};

New format:

CC   -!- MASS SPECTROMETRY: [Isoform 3]: Mass=32875.93; Method=MALDI;
CC       Evidence={ECO:0000269|PubMed:11840567};

RNA EDITING

Example: Q9P225

CC   -!- ALTERNATIVE PRODUCTS:
...
CC       Name=3;
CC         IsoId=Q9P225-3; Sequence=VSP_031913, VSP_031914, VSP_031915;

Previous format:

CC   -!- RNA EDITING: Modified_positions=Not_applicable; Note=Exon 13
CC       included in isoform 3 is extensively edited in brain.
CC       {ECO:0000269|PubMed:20835228};

New format:

CC   -!- RNA EDITING: [Isoform 3]: Modified_positions=Not_applicable; Note=Exon
CC       13 is extensively edited in brain. {ECO:0000269|PubMed:20835228};

WEB RESOURCE

Example: P50570

CC   -!- ALTERNATIVE PRODUCTS:
...
CC       Name=1;
CC         IsoId=P50570-1; Sequence=Displayed;

Previous format:

CC   -!- WEB RESOURCE: Name=The UMD-DNM2-isoform 1 mutations database;
CC       URL="http://www.umd.be/DNM2/";

New format:

CC   -!- WEB RESOURCE: [Isoform 1]: Name=The UMD-DNM2-isoform 1 mutations
CC       database;
CC       URL="http://www.umd.be/DNM2/";

CATALYTIC ACTIVITY

Example: Q2YHF0

FT   CHAIN      1475   2092       Serine protease NS3.
FT                                {ECO:0000250|UniProtKB:P29990}.
FT                                /FTId=PRO_0000268140.
...
FT   CHAIN      2488   3387       RNA-directed RNA polymerase NS5.
FT                                {ECO:0000250|UniProtKB:P29990}.
FT                                /FTId=PRO_0000268144.

Previous format:

CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=Selective hydrolysis of -Xaa-Xaa-|-Yaa- bonds in which
CC         each of the Xaa can be either Arg or Lys and Yaa can be either
CC         Ser or Ala.; EC=3.4.21.91;
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a ribonucleoside 5'-triphosphate + RNA(n) = diphosphate +
CC         RNA(n+1); Xref=Rhea:RHEA:21248, Rhea:RHEA-COMP:11128, Rhea:RHEA-
CC         COMP:11129, ChEBI:CHEBI:33019, ChEBI:CHEBI:61557,
CC         ChEBI:CHEBI:83400; EC=2.7.7.48; Evidence={ECO:0000255|PROSITE-
CC         ProRule:PRU00539};

New format:

CC   -!- CATALYTIC ACTIVITY: [Serine protease NS3]:
CC       Reaction=Selective hydrolysis of -Xaa-Xaa-|-Yaa- bonds in which each of
CC         the Xaa can be either Arg or Lys and Yaa can be either Ser or Ala.;
CC         EC=3.4.21.91;
CC   -!- CATALYTIC ACTIVITY: [RNA-directed RNA polymerase NS5]:
CC       Reaction=a ribonucleoside 5'-triphosphate + RNA(n) = diphosphate +
CC         RNA(n+1); Xref=Rhea:RHEA:21248, Rhea:RHEA-COMP:11128, Rhea:RHEA-
CC         COMP:11129, ChEBI:CHEBI:33019, ChEBI:CHEBI:61557, ChEBI:CHEBI:83400;
CC         EC=2.7.7.48; Evidence={ECO:0000255|PROSITE-ProRule:PRU00539};

COFACTOR

Please note that the previous text format of COFACTOR annotations already allowed to describe a product by its name in the optional first field. To be consistent with all other annotation types we have added square brackets around the product name.

Example: P26662

FT   CHAIN      1027   1657       Serine protease NS3. {ECO:0000255}.
FT                                /FTId=PRO_0000037644.
FT   CHAIN      1658   1711       Non-structural protein 4A. {ECO:0000255}.
FT                                /FTId=PRO_0000037645.

Previous format:

CC   -!- COFACTOR: Serine protease NS3:
CC       Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC         Evidence={ECO:0000269|PubMed:9060645};
CC       Note=Binds 1 zinc ion. {ECO:0000269|PubMed:9060645};
CC   -!- COFACTOR: Non-structural protein 5A:
CC       Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000250};
CC       Note=Binds 1 zinc ion in the NS5A N-terminal domain.
CC       {ECO:0000250};

New format:

CC   -!- COFACTOR: [Serine protease NS3]:
CC       Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC         Evidence={ECO:0000269|PubMed:9060645};
CC       Note=Binds 1 zinc ion. {ECO:0000269|PubMed:9060645};
CC   -!- COFACTOR: [Non-structural protein 5A]:
CC       Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000250};
CC       Note=Binds 1 zinc ion in the NS5A N-terminal domain. {ECO:0000250};

BIOPHYSICOCHEMICAL PROPERTIES

Example: Q9ULC5

CC   -!- ALTERNATIVE PRODUCTS:
...
CC       Name=1; Synonyms=ACSL5b, ACSL5-fl;
CC         IsoId=Q9ULC5-1; Sequence=Displayed;
...
CC       Name=3; Synonyms=ACSL5delta20;
CC         IsoId=Q9ULC5-4; Sequence=VSP_038233;

Previous format:

CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       Kinetic parameters:
CC         KM=0.11 uM for palmitic acid (isoform 1 at pH 7.5)
CC         {ECO:0000269|PubMed:17681178};
CC         KM=0.38 uM for palmitic acid (isoform 1 at pH 9.5)
CC         {ECO:0000269|PubMed:17681178};
CC         KM=0.04 uM for palmitic acid (isoform 3 at pH 7.5)
CC         {ECO:0000269|PubMed:17681178};
CC         KM=0.15 uM for palmitic acid (isoform 3 at pH 8.5)
CC         {ECO:0000269|PubMed:17681178};
CC       pH dependence:
CC         Optimum pH is 9.5 (isoform 1), 7.5-8.5 (isoform 3).
CC         {ECO:0000269|PubMed:17681178};

New format:

CC   -!- BIOPHYSICOCHEMICAL PROPERTIES: [Isoform 1]:
CC       Kinetic parameters:
CC         KM=0.11 uM for palmitic acid (at pH 7.5)
CC         {ECO:0000269|PubMed:17681178};
CC         KM=0.38 uM for palmitic acid (at pH 9.5)
CC         {ECO:0000269|PubMed:17681178};
CC       pH dependence:
CC         Optimum pH is 9.5. {ECO:0000269|PubMed:17681178};
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES: [Isoform 3]:
CC       Kinetic parameters:
CC         KM=0.04 uM for palmitic acid (at pH 7.5)
CC         {ECO:0000269|PubMed:17681178};
CC         KM=0.15 uM for palmitic acid (at pH 8.5)
CC         {ECO:0000269|PubMed:17681178};
CC       pH dependence:
CC         Optimum pH is 7.5-8.5. {ECO:0000269|PubMed:17681178};

SEQUENCE CAUTION

Example: Q9NQS3

Previous format:

CC   -!- ALTERNATIVE PRODUCTS:
...
CC       Name=1;
CC         IsoId=Q9NQS3-1; Sequence=Displayed;
...
CC       Name=3;
CC         IsoId=Q9NQS3-3; Sequence=VSP_046893, VSP_046894;
CC         Note=Ref.2 (BAC11404) sequence differs from that shown due to
CC         erroneous termination (Truncated C-terminus). {ECO:0000305};
...
CC   -!- SEQUENCE CAUTION:
CC       Sequence=AAH17572.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};

New format:

CC   -!- ALTERNATIVE PRODUCTS:
...
CC       Name=1;
CC         IsoId=Q9NQS3-1; Sequence=Displayed;
...
CC       Name=3;
CC         IsoId=Q9NQS3-3; Sequence=VSP_046893, VSP_046894;
...
CC   -!- SEQUENCE CAUTION: [Isoform 1]:
CC       Sequence=AAH17572.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC   -!- SEQUENCE CAUTION: [Isoform 3]:
CC       Sequence=BAC11404.1; Type=Erroneous termination; Note=Truncated C-terminus.; Evidence={ECO:0000305};

FT section

Note: The format descriptions make use of POSIX ERE syntax.

All positional annotations in the FT section previously referred to the canonical sequence that is shown in the UniProtKB entry. This was the text format of these annotation types:

FT   <TYPE>      <B>    <E>       (<Description>.)?( {<Evidences>}.)?
(FT                                /FTId=<Id>.)?

Where

• <TYPE> is a value from the controlled vocabulary of positional annotation types.
• <B> and <E> are amino acid positions on the canonical sequence. For most annotation types, they are the begin and end position of a sequence range, but they have other semantics for some types (e.g. CROSSLNK and DISULFID).
• <Description> may provide information in addition to that conveyed by the <TYPE> and the location <B> and <E>. This field is mandatory for some annotation types and optional for others.
• <Evidences> are optional and added between curly braces.
• <Id> is a unique annotation identifier that is mandatory for some annotation types, including CHAIN and PEPTIDE where it corresponds to the <ProductId>.

We have modified this format in order to describe amino acid positions on isoforms sequences. The new format is inspired by the INSDC's feature table format to enable code reuse:

FT   <TYPE>          <Location>
(FT                   /<Qualifier>(="<Value>")?)*

Where

• <TYPE> is a value from the controlled vocabulary of positional annotation types.
• <Location> is a sequence location on the canonical or an isoform sequence. We will use for now only a subset of the INSDC Location types: A <Location> must be either a single <Position> or a range of <Position> that may optionally be preceded by an isoform ID. The < and > symbols may be used with begin and end positions to indicate that the begin or end point is beyond the specified amino acid position. Please note that we have to extend the INSDC Location format with the ? symbol to allow us to represent all existing UniProtKB locations. This symbol may precede a <Position> to indicate that the exact position is unsure, or it may substitute the <Position> when the position is unknown.

  (<IsoformId>:)?((<|?)?<Position>|?)(..((>|?)?<Position>|?))?
  

• /<Qualifier> may provide information in addition to that conveyed by the <TYPE> and <Location>. While we will follow the format of the INSDC Qualifiers, we will introduce our own <Qualifier> types where necessary. For this format change, we will represent the existing data with 3 qualifiers:
  • /note= will show the content of the current <Description> field.
  • /evidence= will show the content of the current <Evidences> field.
  • /id= will show the content of the current /FTId= field.

In a future format change, we may introduce more <Location> and <Qualifier> types to structure the description of positional annotations further.

Lines are wrapped at 80 chars (see section Change of line length in UniProtKB text format above).

Example: P84077

This example illustrates the format change with a selection of representative positional annotation types that refer to the canonical sequence.

Previous format:

FT   INIT_MET      1      1       Removed. {ECO:0000244|PubMed:19413330,
FT                                ECO:0000244|PubMed:22223895,
FT                                ECO:0000269|PubMed:25255805,
FT                                ECO:0000269|PubMed:25807930}.
FT   CHAIN         2    181       ADP-ribosylation factor 1.
FT                                /FTId=PRO_0000207378.
...
FT   NP_BIND     126    129       GTP. {ECO:0000244|PDB:1HUR,
FT                                ECO:0000244|PDB:1RE0,
FT                                ECO:0000244|PDB:1U81,
FT                                ECO:0000244|PDB:3O47, ECO:0000305}.
...
FT   VARIANT      35     35       Y -> H (in PVNH8; decreased interaction
FT                                with GGA3; dbSNP:rs879036238).
FT                                {ECO:0000269|PubMed:28868155}.
FT                                /FTId=VAR_081272.
...
FT   HELIX         6      9       {ECO:0000244|PDB:1HUR}.

New format:

FT   INIT_MET        1
FT                   /note="Removed"
FT                   /evidence="ECO:0000244|PubMed:19413330,
FT                   ECO:0000244|PubMed:22223895, ECO:0000269|PubMed:25255805,
FT                   ECO:0000269|PubMed:25807930"
FT   CHAIN           2..181
FT                   /note="ADP-ribosylation factor 1"
FT                   /id="PRO_0000207378"
...
FT   NP_BIND         126..129
FT                   /note="GTP"
FT                   /evidence="ECO:0000244|PDB:1HUR, ECO:0000244|PDB:1RE0,
FT                   ECO:0000244|PDB:1U81, ECO:0000244|PDB:3O47, ECO:0000305"
...
FT   VARIANT         35
FT                   /note="Y -> H (in PVNH8; decreased interaction with GGA3;
FT                   dbSNP:rs879036238)"
FT                   /evidence="ECO:0000269|PubMed:28868155"
FT                   /id="VAR_081272"
...
FT   HELIX           6..9
FT                   /evidence="ECO:0000244|PDB:1HUR"

Example: P0C551

This example illustrates the use of the < and ? symbols in UniProtKB locations.

Previous format:

FT   SIGNAL       <1      ?       {ECO:0000250}.
FT   PROPEP        ?     17       {ECO:0000250}.
FT                                /FTId=PRO_0000293097.
FT   CHAIN        18    142       Acidic phospholipase A2 KBf-grIB.
FT                                /FTId=FTId=PRO_0000293098.

New format:

FT   SIGNAL          <1..?
FT                   /evidence="ECO:0000250"
FT   PROPEP          ?..17
FT                   /evidence="ECO:0000250"
FT                   /id="PRO_0000293097"
FT   CHAIN           18..142
FT                   /note="Acidic phospholipase A2 KBf-grIB"
FT                   /id="PRO_0000293098"

Example: P12821

This example illustrates how positional annotations for isoforms are represented.

Previous format:

CC   -!- ALTERNATIVE PRODUCTS:
CC       ...
CC       Name=Testis-specific; Synonyms=ACE-T;
CC         IsoId=P12821-3, P22966-1;
CC         Sequence=VSP_035120, VSP_035121;
CC         Note=Variant in position: 32:S->P (in dbSNP:rs4317). Variant in
CC         position: 49:S->G (in dbSNP:rs4318).;
...
FT   VARIANT     154    154       A -> T (in dbSNP:rs13306087).
FT                                /FTId=VAR_029139.

New format:

CC   -!- ALTERNATIVE PRODUCTS:
CC       ...
CC       Name=Testis-specific; Synonyms=ACE-T;
CC         IsoId=P12821-3, P22966-1;
CC         Sequence=VSP_035120, VSP_035121;
...
FT   VARIANT         154
FT                   /note="A -> T (in dbSNP:rs13306087)"
FT                   /id="VAR_029139"
...
FT   VARIANT         P12821-3:32
FT                   /note="S -> P (in dbSNP:rs4317)"
FT                   /id="VAR_x"
FT   VARIANT         P12821-3:49
FT                   /note="S -> G (in dbSNP:rs4318)"
FT                   /id="VAR_y"

XML format

The UniProtKB XSD already allowed to describe the product to which an annotation applies and required no changes.

Isoforms are described in "alternative products" annotations. The products of proteolytic cleavage are described in "peptide" and "chain" annotations. All three annotation types provide a name (<ProductName>) and/or a unique ID (<ProductId>) for the product that they describe:

• "alternative products" annotations describe each isoform by an isoform element of isoformType. The isoformType describes the product IDs and names with sequences of id and name elements (where the first element in each sequence is the main product ID/name).

  <comment type="alternative products">
    ...
    <isoform>
      <id><ProductId></id>
      <id><OldProductId></id>
      <name><ProductName></name>
      <name><AlternativeProductName></name>
      ...
    </isoform>
    ...
  </comment>
  

• "peptide" and "chain" annotations show the name and ID of a proteolytic cleavage product in the description and id attributes of the featureType.

  <feature type="chain" description="<ProductName>" id="<ProductId>">
  ...
  </feature>
  

commentType

The commentType has two ways to indicate that the annotation applies to a specific product:

• An optional molecule element of moleculeType allows to describe a product by its name or/and unique ID. It is currently only used for "subcellular location" and "cofactor" annotations (see examples below). In the future it may be used for all annotations that are represented by commentType.

• An optional sequence of location elements of locationType allows to describe the sequence coordinates of an annotation. The locationType has an optional sequence attribute that is only set (to an isoform ID) when the coordinates are not for the canonical sequence. Sequence coordinates may currently be given for "rna editing", "sequence caution" and "mass spectrometry" annotations. In the future sequence caution and mass spectrometry annotations will no longer describe sequence coordinates.

subcellular location

Example: Q13421

<comment type="alternative products">
  ...
  <isoform>
    <id>Q13421-2</id>
    <name>3</name>
    <name>SMRP</name>
    <sequence type="described" ref="VSP_021059 VSP_021060"/>
    ...
  </isoform>
  ...
</comment>
...
<feature type="chain" description="Megakaryocyte-potentiating factor"
                      id="PRO_0000253560">
  <location>
    <begin position="37"/>
    <end position="286"/>
  </location>
</feature>

<comment type="subcellular location">
  <subcellularLocation>
    <location>Cell membrane</location>
    <topology>Lipid-anchor</topology>
    <topology>GPI-anchor</topology>
  </subcellularLocation>
  <subcellularLocation>
    <location>Golgi apparatus</location>
  </subcellularLocation>
</comment>
<comment type="subcellular location">
  <molecule>Megakaryocyte-potentiating factor</molecule>
  <subcellularLocation>
    <location>Secreted</location>
  </subcellularLocation>
</comment>
<comment type="subcellular location">
  <molecule>Isoform 3</molecule>
  <subcellularLocation>
    <location>Secreted</location>
  </subcellularLocation>
</comment>

cofactor

Example: P26662

<feature type="chain" description="Serine protease NS3"
                      id="PRO_0000037644" evidence="4">
  <location>
    <begin position="1027"/>
    <end position="1657"/>
  </location>
</feature>
<feature type="chain" description="Non-structural protein 4A"
                      id="PRO_0000037645" evidence="4">
  <location>
    <begin position="1658"/>
    <end position="1711"/>
  </location>
</feature>

<comment type="cofactor">
  <molecule>Serine protease NS3</molecule>
  <cofactor evidence="14">
    <name>Zn(2+)</name>
    <dbReference type="ChEBI" id="CHEBI:29105"/>
  </cofactor>
  <text evidence="14">Binds 1 zinc ion.</text>
</comment>
<comment type="cofactor">
  <molecule>Non-structural protein 5A</molecule>
  <cofactor evidence="3">
    <name>Zn(2+)</name>
    <dbReference type="ChEBI" id="CHEBI:29105"/>
  </cofactor>
  <text evidence="3">Binds 1 zinc ion in the NS5A N-terminal domain.</text>
</comment>

featureType

The featureType has a mandatory location element of locationType to describe the sequence coordinates of an annotation.

Example: P84077

<feature type="initiator methionine" description="Removed" evidence="6 7 21 22">
  <location>
    <position position="1"/>
  </location>
</feature>
<feature type="chain" description="ADP-ribosylation factor 1" id="PRO_0000207378">
  <location>
    <begin position="2"/>
    <end position="181"/>
  </location>
</feature>
...
<feature type="nucleotide phosphate-binding region" description="GTP" evidence="1 2 3 4 25">
  <location>
    <begin position="126"/>
    <end position="129"/>
  </location>
</feature>
...
<feature type="sequence variant" description="In PVNH8; decreased interaction with GGA3; dbSNP:rs879036238." id="VAR_081272" evidence="23">
  <original>Y</original>
  <variation>H</variation>
  <location>
    <position position="35"/>
  </location>
</feature>
...
<feature type="helix" evidence="1">
  <location>
    <begin position="6"/>
    <end position="9"/>
  </location>
</feature>

The locationType has an optional sequence attribute that is only set (to an isoform ID) when the coordinates are not for the canonical sequence.

Example: P12821

Previous representation:

<comment type="alternative products">
  ...
  <isoform>
    <id>P12821-3</id>
    <id>P22966-1</id>
    <name>Testis-specific</name>
    <name>ACE-T</name>
    <sequence type="described" ref="VSP_035120 VSP_035121"/>
    <text>Variant in position: 32:S->P (in dbSNP:rs4317). Variant in position: 49:S->G (in dbSNP:rs4318).</text>
  </isoform>
  ...
</comment>
...
<feature type="sequence variant" description="In dbSNP:rs13306087." id="VAR_029139">
  <original>A</original>
  <variation>T</variation>
  <location>
    <position position="154"/>
  </location>
</feature>

New representation:

<comment type="alternative products">
  ...
  <isoform>
    <id>P12821-3</id>
    <id>P22966-1</id>
    <name>Testis-specific</name>
    <name>ACE-T</name>
    <sequence type="described" ref="VSP_035120 VSP_035121"/>
  </isoform>
  ...
</comment>
...
<feature type="sequence variant" description="In dbSNP:rs13306087." id="VAR_029139">
  <original>A</original>
  <variation>T</variation>
  <location>
    <position position="154"/>
  </location>
</feature>
...
<feature type="sequence variant" description="In dbSNP:rs4317." id="VAR_x">
  <original>S</original>
  <variation>P</variation>
  <location sequence="P12821-3">
    <position position="32"/>
  </location>
</feature>
<feature type="sequence variant" description="In dbSNP:rs4318." id="VAR_y">
  <original>S</original>
  <variation>G</variation>
  <location sequence="P12821-3">
    <position position="49"/>
  </location>
</feature>

RDF format

The UniProt RDF schema ontology already allowed to describe the product to which an annotation applies and required no changes for this purpose.

The RDF format has a single hierarchy of Annotation classes with various intermediary classes. The subclass Sequence_Annotation groups all classes that refer to a location on a protein sequence. This location is represented with FALDO and always indicates the FALDO reference sequence for the location (the RDF format makes no special case for a canonical sequence). Annotations that do not refer to a specific location on a protein sequence, but that apply to a given product, describe the sequence of this product with a sequence property. The object of this property may be a Sequence or a Chain_Annotation / Peptide_Annotation that describes a sequence that is the product of proteolytic processing.

Please note that the change of mass spectrometry annotations required an adaptation of the hierarchy of Annotation classes: The Mass_Spectrometry_Annotation class no longer is an rdfs:subClassOf of the Sequence_Annotation class, but a direct rdfs:subClassOf of the Annotation class.

Example: Q13421

@prefix up: <http://purl.uniprot.org/core/> .
@prefix uniprot: <http://purl.uniprot.org/uniprot/> .
@prefix isoform: <http://purl.uniprot.org/isoforms/> .
@prefix annotation: <http://purl.uniprot.org/annotation/> .
@prefix faldo: <http://biohackathon.org/resource/faldo#> .

uniprot:Q13421
  up:annotation
    annotation:PRO_0000253560 ,
    <Q13421#SIPADAC7D651EFC09CC> ,
    <Q13421#SIP307BEB951103B073> ,
    <Q13421#SIPB6746E472B99B031> ,
    ...
  up:sequence
    isoform:Q13421-1 ,
    isoform:Q13421-3 ,
    isoform:Q13421-2 ,
    isoform:Q13421-4 ;

annotation:PRO_0000253560
  rdf:type up:Chain_Annotation ;
  rdfs:comment "Megakaryocyte-potentiating factor" ;
  up:range range:22853569102360878tt37tt286 .
range:22853569102360878tt37tt286
  rdf:type faldo:Region ;
  faldo:begin position:22853569102360878tt37 ;
  faldo:end position:22853569102360878tt286 .
position:22853569102360878tt37
  rdf:type faldo:Position , faldo:ExactPosition ;
  faldo:position 37 ;
  faldo:reference isoform:Q13421-1 .
position:22853569102360878tt286
  rdf:type faldo:Position , faldo:ExactPosition ;
  faldo:position 286 ;
  faldo:reference isoform:Q13421-1 .

<Q13421#SIPADAC7D651EFC09CC>
  rdf:type up:Subcellular_Location_Annotation ;
  up:locatedIn <Q13421#SIP04927440DF8EB941> ,
               <Q13421#SIP727DF431EB6C89EC> .

<Q13421#SIP307BEB951103B073>
  rdf:type up:Subcellular_Location_Annotation ;
  up:locatedIn <Q13421#SIPD59D33F5047A94FD> ;
  up:sequence annotation:PRO_0000253560 .

<Q13421#SIPB6746E472B99B031>
  rdf:type up:Subcellular_Location_Annotation ;
  up:locatedIn <Q13421#SIPD59D33F5047A94FD> ;
  up:sequence isoform:Q13421-2 .

isoform:Q13421-1
  rdf:type up:Simple_Sequence ;
  up:modified "2006-10-17"^^xsd:date ;
  up:version 2 ;
  up:precursor true ;
  up:mass 68986 ;
  up:crc64Checksum "FA17E3609B6CC9CA"^^xsd:token ;
  up:name "1" ;
  rdf:value "MALPTARPLLGSCGTPALGSLLFLLFSL ... LLASTLA" .
isoform:Q13421-3
  rdf:type up:Modified_Sequence ;
  up:name "2" ;
  up:basedOn isoform:Q13421-1 ;
  up:modification annotation:VSP_021059 .
  rdf:value "MALPTARPLLGSCGTPALGSLLFLLFSL ... LLASTLA" ;
isoform:Q13421-2
  rdf:type up:Modified_Sequence ;
  up:name "3" , "SMRP" ;
  up:basedOn isoform:Q13421-1 ;
  up:modification annotation:VSP_021059 , annotation:VSP_021060 .
  rdf:value "MALPTARPLLGSCGTPALGSLLFLLFSL ... LRAPLPC" ;
isoform:Q13421-4
  rdf:type up:Modified_Sequence ;
  up:name "4" ;
  up:basedOn isoform:Q13421-1 ;
  up:modification annotation:VSP_021058 , annotation:VSP_021059 .
  rdf:value "MALPTARPLLGSCGTPALGSLLFLLFSL ... LLASTLA" ;

Cross-references to RNAct

Cross-references have been added to RNAct, a database of protein-RNA interaction predictions for model organisms with supporting experimental data.

RNAct is available at https://rnact.crg.eu.

The format of the explicit links is:

Resource abbreviation	RNAct
Resource identifier	UniProtKB accession number
Optional information 1	Molecule type

Example: Q9Y2I1

Show all entries having a cross-reference to RNAct.

Text format

Example: Q9Y2I1

DR   RNAct; Q9Y2I1; protein.

XML format

Example: Q9Y2I1

<dbReference type="RNAct" id="Q9Y2I1">
   <property type="molecule type" value="protein"/>
</dbreference>

RDF format

Example: Q9Y2I1

uniprot:Q9Y2I1
  rdfs:seeAlso <http://purl.uniprot.org/rnact/Q9Y2I1> .
<http://purl.uniprot.org/rnact/Q9Y2I1>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/RNAct> ;
  rdfs:comment "protein" .

Change of the cross-references to Pharos

We have introduced an additional field in the cross-references to the Pharos database to indicate the development status of a target. Targets are categorized into four development/druggability levels (TDLs), ranging from Tclin for approved drugs with known mechanisms of action, to Tdark for targets about which virtually nothing is known.

Text format

Example: P33151

DR   Pharos; P33151; Tbio.

XML format

Example: P33151

<dbReference type="Pharos" id="P33151">
  <property type="development level" value="Tbio"/>
</dbReference>

This change does not affect the XSD, but may nevertheless require code changes.

RDF format

Example: P33151

uniprot:P33151
  rdfs:seeAlso <http://purl.uniprot.org/pharos/P33151> .
<http://purl.uniprot.org/pharos/P33151>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/Pharos> ;
  rdfs:comment "Tbio" .

Removal of the cross-references to PMAP-CutDB

Cross-references to PMAP-CutDB have been removed.

Changes to the controlled vocabulary of human diseases

New diseases:

• Congenital disorder of glycosylation 1CC
• Epilepsy, idiopathic generalized 16
• Epileptic encephalopathy, early infantile, 78
• Epileptic encephalopathy, early infantile, 79
• Epileptic encephalopathy, early infantile, 80
• Glycosylphosphatidylinositol biosynthesis defect 21
• Hypothyroidism, congenital, non-goitrous, 7
• Hypothyroidism, congenital, non-goitrous, 8
• Hypothyroidism, congenital, non-goitrous, 9
• Intellectual developmental disorder 60 with seizures
• Mental retardation, X-linked, syndromic, 36
• Mitochondrial DNA depletion syndrome 17
• Myopathy, congenital, progressive, with scoliosis
• Nephrotic syndrome 21
• Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly
• Neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies
• Neurodevelopmental disorder with cerebellar hypoplasia and spasticity
• Neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities
• Neurodevelopmental disorder with structural brain anomalies and dysmorphic facies
• Spastic tetraplegia and axial hypotonia, progressive

Changes to the controlled vocabulary for PTMs

New term for the feature key 'Cross-link' ('CROSSLNK' in the flat file):

• 6-(S-cysteinyl)-8alpha-(pros-histidyl)-FAD (Cys-His)

Changes to keywords

Deleted keyword:

• Complete proteome

Proteomes changes

The UniProt Proteomes portal is offering protein sequence sets obtained from the translation of sequenced genomes. Published genomes from NCBI Genome used to be brought into UniProt if they satisfied the following criteria:

• The genome is annotated and a set of coding sequences is available.
• The number of predicted coding sequences falls within a statistically significant range of published proteomes from neighbouring species.

We have changed these criteria to publish all proteomes that can be derived from NCBI genomes that are not considered to be low quality assemblies. We now use a subset of the RefSeq reasons to exclude a genome assembly to determine which proteomes to bring into UniProtKB and we give the reason(s) why a proteome is excluded from UniProtKB. We also provide two metrics to help users to assess the quality of a proteome:

• A score obtained with the BUSCO software.
• A score based on the number of coding sequences expected based on neighbouring species, "Complete Proteome Detector (CPD)".

The "Complete proteome" keyword was removed from all UniProtKB entries. Individual proteomes can be retrieved from the UniProt website by their unique proteome identifier, e.g. UP000005640.

Headline

A scorpion venom toxin may help unravel the mystery of chronic pain

The old saying goes 'an ounce of prevention is worth a pound of cure’, and indeed, our body has developed various strategies to alert us of potential dangers to avoid. One contributor to this strategy is TRPA1, also called the 'wasabi receptor'. TRPA1, a member of the transient receptor family (TRP), is a plasma membrane cation channel expressed by primary afferent sensory neurons. It is activated by chemically reactive electrophiles present in a range of environmental irritants and endogenous inflammatory agents. Cigarette smoke, for example, is rich in reactive electrophiles that can trigger TRPA1 in the cells that line the airways, inducing coughing and sustained airway inflammation. Some plants, such as mustard, wasabi or onions, have evolved compounds that activate TRPA1, possibly to ward off animals that might otherwise eat them. In this context, TRPA1 activation is responsible for the sinus-jolting sting of wasabi and the flood of tears associated with chopping onions.

Not only plants produce TRPA1 activating compounds. Black rock scorpions do too, as has been reported in a recent publication by Lin King et al. This comes as a surprise. Most animal toxins identified so far target voltage-gated ion channels, and the few known to act on TRP channels all activate the capsaicin receptor, TRPV1. The newly discovered black rock scorpion toxin has been called Wasabi receptor toxin or WaTx. In its mature form, it is a 19 amino acid-long peptide, which has the amazing ability to penetrate cells by passive diffusion. This property is not unique to WaTx, other proteins, such as HIV Tat or Drosophila penetratin also share it, but WaTx does not have any sequence similarity to them.

Once in the cell, WaTx binds TRPA1 at the same site as plant and environmental irritants, but the similarity ends there. Reactive electrophiles covalently bind TRPA1 and produce a large increase in the probability of channel opening characterized by brief transitions between open and closed states. This results in the influx of sodium and calcium ions. The influx of Ca(2+), in turn, causes the exocytosis of dense-core vesicles, the release of calcitonin-gene-related peptide (CGRP) and substance P, and ultimately induces neurogenic inflammation. WaTx non-covalent binding to TRPA1 stabilizes the open state of the channel and prolongs open time. Consequently, it induces neuronal depolarization and subsequent hypersensitivities, which are characteristic of chronic pain. In addition, it decreases the relative Ca(2+)-permeability of the channel. The Ca(+2) influx is not sufficient to trigger CGRP release and does not cause any inflammation. These observations show a striking convergent evolution between plants and animals in terms of binding site, resulting, however, in a very different modulation of cation channel activity and a distinct outcome in terms of inflammation.

TRPA1 is expressed in virtually every animal, from worms and humans, but WaTx only activates mammalian orthologs. Why so? It is difficult to say. Black rock scorpions feed on insects like cockroaches and beetles, as well as other small invertebrates such as millipedes, centipedes, spiders and rarely earthworms, but never mammals. Therefore, WaTx may have a deterrent role aimed specifically at mammalian predators.

One thing is certain: with WaTx, scorpions provide us with a powerful tool to study the central neural pathways contributing to chronic pain and to investigate the link between chronic pain and inflammation. TRPA1 is emerging as a potential target for new classes of non-opioid analgesics to treat chronic pain.

As of this release, WaTx has been annotated and is painlessly available in UniProtKB/Swiss-Prot.

UniProtKB news

Removal of the cross-references to EcoGene

Cross-references to EcoGene have been removed.

Change of the cross-references to DisProt

Cross-references to DisProt may now be isoform-specific. The general format of isoform-specific cross-references was described in release 2014_03.

Example: Q9NQC3

Changes to the controlled vocabulary of human diseases

New diseases:

• Deafness, autosomal dominant, 37
• Ectodermal dysplasia 15, hypohidrotic/hair type
• Epilepsy, rolandic, with proxysmal exercise-induce dystonia and writer's cramp
• Epileptic encephalopathy, early infantile, 77
• Erythrokeratodermia variabilis et progressiva 6
• Hepatitis, fulminant viral
• Hyper-IgE recurrent infection syndrome 4, autosomal recessive
• Hypoalphalipoproteinemia, primary, 2
• Hypopigmentation, organomegaly, and delayed myelination and development
• Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facies
• Immunodeficiency 64
• Microangiopathy and leukoencephalopathy, pontine, autosomal dominant
• Mitochondrial DNA depletion syndrome 16, hepatic type
• Myopathy, congenital, with tremor
• Neurodevelopmental disorder with visual defects and brain anomalies
• Night blindness, congenital stationary, 1I
• Oculoectodermal syndrome
• Oocyte maturation defect 7
• Pseudofolliculitis barbae
• Robinow syndrome, autosomal recessive 2
• Trichothiodystrophy 7, non-photosensitive
• Van Esch-O'Driscoll syndrome

Changes in subcellular location controlled vocabulary

New subcellular locations:

• Neuronal dense core vesicle
• Neuronal dense core vesicle membrane
• Postsynaptic early endosome
• Postsynaptic early endosome membrane
• Postsynaptic endocytic zone
• Postsynaptic endosome
• Postsynaptic Golgi apparatus
• Postsynaptic recycling endosome
• Postsynaptic recycling endosome membrane
• Presynaptic active zone membrane
• Presynaptic endocytic zone
• Presynaptic endosome
• Spine apparatus
• Synaptic cell membrane

Headline

Biological weapons in the struggle for life

The apoplast, the extracellular space between plant cells, is a battleground between plants and attacking microorganisms. The battle often starts with the secretion of carbohydrate-degrading enzymes by the invader and a counter-attack by the plant with dedicated enzyme inhibitors. This happens for instance when Phytophthora sojae invades soybean. During very early infection stages (20 minutes to 2 hours), the oomycete expresses and secretes high levels of a xyloglucanase enzyme, called XEG1. XEG1 degrades the plant cell wall polymers and not only permits pathogen invasion, but also provides it with nutrients. XEG1 expression declines rapidly from 3 hours onwards.

Like other plants, soybean monitors the apoplastic environment through pattern recognition receptors and recognizes XEG1 as a PAMP (pathogen-associated molecular pattern). This recognition triggers defense responses, which include the secretion of GIP1, a xyloglucanase inhibitor. Efficient XEG1 inhibition by GIP1 increases soybean resistance towards P. sojae. This could be the end of the story, but P. sojae has another trick up its sleeve.

When Ma et al. studied GIP1 binding to XEG1 paralogs, they retrieved only one protein, called XLP1, in addition to XEG1. Like XEG1, XLP1 is targeted to the apoplast. It also shows a similar expression time course to XEG1, i.e. high levels during very early infection stages, followed by a rapid decline, suggesting a role in virulence. Unlike XEG1, however, XLP1 does not show any xyloglucanase activity. It is 52 residues shorter and is missing one of the residues critical for xyloglucanase activity. XLP1 contributes to P. sojae infectivity, but only in the presence of active XEG1. Thus XLP1 acts as a decoy to disrupt plant defenses. It interacts with GIP1 with a five-fold higher affinity than that of XEG1 and hence neutralizes the GIP1 inhibitor. In this setting, XEG1 can pursue plant cell wall digestion without any hindrance.

The 3 belligerent proteins have been annotated in UniProtKB/Swiss-Prot and are publicly available.

UniProtKB news

Change of annotation topic 'Sequence caution'

The annotation topic Sequence caution reports differences between the protein sequence shown in a UniProtKB entry and other available protein sequences derived from the same gene. It indicates the likely cause for the differences, and when that cause is a frameshift or erroneous termination, the amino acid sequence position(s) of these errors were listed when possible. Since it is nowadays easy to align two protein sequences for comparison, we no longer curate error positions and removed the field where this information was stored.

Text format

We removed the optional Positions field.

Example: P14332

Previous format:

CC   -!- SEQUENCE CAUTION: Sequence=CAA34633.1; Type=Frameshift; Positions=226, 249; Evidence={ECO:0000305};

New format:

CC   -!- SEQUENCE CAUTION: Sequence=CAA34633.1; Type=Frameshift; Evidence={ECO:0000305};

XML format

This change did not affect the UniProtKB XSD.

Example: P14332

Previous format:

<comment type="sequence caution" evidence="3">
  <conflict type="frameshift">
    <sequence resource="EMBL-CDS" id="CAA34633" version="1"/>
  </conflict>
  <location>
    <position position="226"/>
  </location>
  <location>
    <position position="249"/>
  </location>
</comment>

New format:

<comment type="sequence caution" evidence="3">
  <conflict type="frameshift">
    <sequence resource="EMBL-CDS" id="CAA34633" version="1"/>
  </conflict>
</comment>

RDF format

This change required an adaptation of the hierarchy of Annotation classes in the UniProt RDF schema ontology: The Sequence_Caution_Annotation class is no longer an rdfs:subClassOf of the Sequence_Annotation class, but a direct rdfs:subClassOf of the Annotation class.

Example: P14332

Previous format:

uniprot:P14332
  up:annotation <P14332#SIP7159608509D280BB> .

<P14332#SIPBBAF3CC29FCD3715>
  rdf:type up:Frameshift_Annotation ;
  up:conflictingSequence <P14332#SIPD8B2EDFEB46FA203> ;
  up:range range:22572098403906094tt226tt226 ,
           range:22572098403906094tt249tt249 .
range:22572098403906094tt226tt226
  rdf:type faldo:Region ;
  faldo:begin position:22572098403906094tt226 ;
  faldo:end position:22572098403906094tt226 .
position:22572098403906094tt226
  rdf:type faldo:Position , faldo:ExactPosition ;
  faldo:position 226 ;
  faldo:reference isoform:P14332-1 .
range:22572098403906094tt249tt249
  rdf:type faldo:Region ;
  faldo:begin position:22572098403906094tt249 ;
  faldo:end position:22572098403906094tt249 .
position:22572098403906094tt249
  rdf:type faldo:Position , faldo:ExactPosition ;
  faldo:position 249 ;
  faldo:reference isoform:P14332-1 .

New format:

uniprot:P14332
  up:annotation <P14332#SIP7159608509D280BB> .

<P14332#SIPBBAF3CC29FCD3715>
  rdf:type up:Frameshift_Annotation ;
  up:conflictingSequence <P14332#SIPD8B2EDFEB46FA203> .

Cross-references to PlantReactome

Cross-references have been added to PlantReactome, a curated resource of core pathways and reactions in plant biology.

PlantReactome is available at https://plantreactome.gramene.org

The format of the explicit links is:

Resource abbreviation	PlantReactome
Resource identifier	Resource identifier
Optional information	Pathway name

Example: P0C128

Show all entries having a cross-reference to PlantReactome.

Text format

Example: P0C128

DR   PlantReactome; R-OSA-5608118; Auxin signalling.

XML format

Example: P0C128

<dbReference type="PlantReactome" id="R-OSA-5608118">
  <property type="pathway name" value="Auxin signalling"/>
</dbReference>

RDF format

Example: P0C128

uniprot:P0C128
  rdfs:seeAlso <http://purl.uniprot.org/plantreactome/R-OSA-5608118> .
<http://purl.uniprot.org/plantreactome/R-OSA-5608118>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/PlantReactome> ;
  rdfs:comment "Auxin signalling" .

Change of the cross-references to Reactome

Cross-references to Reactome may now be isoform-specific. The general format of isoform-specific cross-references was described in release 2014_03.

Example: P00167

Changes to the controlled vocabulary of human diseases

New diseases:

• Aortic valve disease 3
• Arthrogryposis multiplex congenita, myogenic type
• Cerebellar atrophy with seizures and variable developmental delay
• Coffin-Siris syndrome 10
• Congenital hypotonia, epilepsy, developmental delay, and digital anomalies
• Contractures, pterygia, and variable skeletal fusions syndrome 1A
• GIST-plus syndrome
• Holoprosencephaly 12 with or without pancreatic agenesis
• Hypotonia, hyperventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalities
• Immunodeficiency 63 with lymphoproliferation and autoimmunity
• Intellectual developmental disorder, autosomal recessive 71
• Intellectual developmental disorder 59
• Leber congenital amaurosis 19
• Nephrotic syndrome 20
• Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities
• Neurodevelopmental disorder with microcephaly and structural brain anomalies
• Neurodevelopmental disorder with seizures and non-epileptic hyperkinetic movements
• Neuropathy, hereditary motor and sensory, 6C, with optic atrophy
• Noonan syndrome 11
• O'Donnell-Luria-Rodan syndrome
• Polydactyly, postaxial, A10
• Shukla-Vernon syndrome
• Spondyloepimetaphyseal dysplasia, sponastrime type

Modified diseases:

• Arthrogryposis, distal, 2B -> Arthrogryposis, distal, 2B1
• Arthrogryposis, distal, 9 -> Contractural arachnodactyly, congenital
• Hyperlipidemia, familial combined -> Hyperlipidemia, familial combined, 3
• Hyperlipidemia combined 1 -> Hyperlipidemia, familial combined, 1
• Kahn-Kahn-Katsanis syndrome -> Khan-Khan-Katsanis syndrome
• Lipoprotein lipase deficiency -> Hyperlipoproteinemia 1
• Mental retardation, X-linked, syndromic, with hypotonic facies 1 -> Mental retardation-hypotonic facies syndrome, X-linked, 1
• Mental retardation, X-linked, ARX-related -> Mental retardation, X-linked, with or without seizures, ARX-related
• Polydactyly preaxial 4 -> Polydactyly, preaxial 4
• Spastic paraplegia 23 -> Spastic paraplegia 23, autosomal recessive

Deleted diseases

• Mental retardation, X-linked 17

Changes to the controlled vocabulary for PTMs

New terms for the feature key 'Cross-link' ('CROSSLNK' in the flat file):

• N5-[4-(S-L-cysteinyl)-5-methyl-1H-imidazol-2-yl]-L-ornithine (Arg-Cys) (interchain with C-...)
• N5-[4-(S-L-cysteinyl)-5-methyl-1H-imidazol-2-yl]-L-ornithine (Cys-Arg) (interchain with R-...)

New term for the feature key 'Glycosylation' ('CARBOHYD' in the flat file):

• N-linked (Glc) (glycation) arginine

New terms for the feature key 'Modified residue' ('MOD_RES' in the flat file):

• S-(2-succinyl)cysteine
• N6-carbamoyllysine
• S-(2,3-dicarboxypropyl)cysteine
• S-cGMP-cysteine

Changes in subcellular location controlled vocabulary

New subcellular locations:

• Neuron projection
• Postsynapse
• Postsynaptic density membrane
• Presynapse
• Presynaptic active zone
• Synaptic cleft

Headline

Magnetic personalities

Magnetotactic bacteria sense and align to the Earth's magnetic field, swimming north in the Northern Hemisphere and south in the Southern in the presence of oxygen. This amazing ability to sense the Earth's magnetic field is provided by small organelles, called magnetosomes, formed by iron nanocrystals of either magnetite (Fe₃O₄) or greigite (Fe₃S₄) surrounded by a phospholipid bilayer. Generally, magnetosomes form chains that align along the long axis of the cell using a dedicated actin-like cytoskeletal structure.

Source: Frank Mickoleit CC BY-SA 3.0

Magnetosome formation is a complex process, which includes invagination of the cell inner membrane to form vesicles, iron ion uptake, crystal biomineralization and magnetosome chain assembly. It involves a large number of proteins, encoded by genes clustered in an approximately 100 kb magnetosome island. Among all proteins involved in magnetosome formation, one of the single most important is MamB, a probable iron transporter with a role in both vesicle formation and biomineralization. MamB is stabilized by heterodimerization with MamM. Studies in genetically tractable Magnetospirillum magneticum (strain AMB-1) and Magnetospirillum gryphiswaldense (strain MSR) have pinpointed the function of many more proteins. For instance, MamA forms a scaffold to which other proteins attach on the organelle's exterior. MamI aids in magnetite nucleation, while MamH is another probable iron transporter. MamN may control the pH of the magnetosome lumen. 4 redox-active multi-heme proteins are probably involved in correct iron oxidization (MamP, MamT, MamX and MamE), the latter is also a protease necessary for magnetosome protein maturation. There are proteins that positively regulate crystal size (including MamC, MamD MamG, MamF and those that negatively regulate crystal size (Mms36 and Mms48). Finally MamK is an actin-like protein involved in organelle positioning, along with MamJ.

The interest in magnetosomes goes far beyond the understanding of these fascinating bacteria. Magnetosomes may be instrumental for the improvement of magnetic nanoparticle biotechnologies. Purified bacterial magnetosomes represent magnetic nanoparticles with exceptionally well-defined characteristics, owing to the precise control that is exerted during all stages of biogenesis, and several unprecedented properties, such as high crystallinity, strong magnetization, and a uniform distribution of shape and size that cannot be replicated by synthesis using abiotic processes. In the biomedical field, promising results suggest that magnetosomes could be used in medical imaging, targeted drug delivery and tumor hyperthermia. In the context of wastewater treatment, it has been shown that heavy metal ions can be adsorbed onto magnetosome-producing microorganisms and then removed by magnetic separation. In addition, it may also help us learn more about the origin of life and the evolution of membrane-bound eukaryotic organelles.

As of this release nearly 70 magnetosome proteins have been annotated and can be retrieved using the term magnetosome.

UniProtKB news

Cross-references to DrugCentral

Cross-references have been added to DrugCentral, an online drug information resource providing information on active ingredients chemical entities, pharmaceutical products, drug mode of action, indications, pharmacologic action.

DrugCentral is available at http://drugcentral.org.

The format of the explicit links is:

Resource abbreviation	DrugCentral
Resource identifier	UniProtKB accession number

Example: P35372

Show all entries having a cross-reference to DrugCentral.

Text format

Example: P35372

DR   DrugCentral; P35372; -.

XML format

Example: P35372

<dbReference type="DrugCentral" id="P35372"/>

RDF format

Example: P35372

uniprot:P35372
  rdfs:seeAlso <http://purl.uniprot.org/drugcentral/P35372> .
<http://purl.uniprot.org/drugcentral/P35372>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/DrugCentral> .

Cross-references to Pharos

Cross-references have been added to Pharos, a user interface to the knowledge-base for the Druggable Genome (DG), whose goal is to illuminate the uncharacterized and/or poorly annotated portion of the DG, focusing on three of the most commonly drug-targeted protein families: G-protein-coupled receptors (GPCRs), ion channels (ICs) and kinases.

Pharos is available at https://pharos.nih.gov.

The format of the explicit links is:

Resource abbreviation	Pharos
Resource identifier	UniProtKB accession number

Example: Q7Z3E2

Show all entries having a cross-reference to Pharos.

Text format

Example: Q7Z3E2

DR   Pharos; Q7Z3E2; -.

XML format

Example: Q7Z3E2

<dbReference type="Pharos" id="Q7Z3E2"/>

RDF format

Example: Q7Z3E2

uniprot:Q7Z3E2
  rdfs:seeAlso <http://purl.uniprot.org/pharos/Q7Z3E2> .
<http://purl.uniprot.org/pharos/Q7Z3E2>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/Pharos> .

Cross-references to MassIVE

Cross-references have been added to MassIVE, a community resource developed by the NIH-funded Center for Computational Mass Spectrometry to promote the global, free exchange of mass spectrometry data and provide a reusable aggregation of community-scale detection of peptides and proteins observations.

MassIVE is available at https://massive.ucsd.edu/.

The format of the explicit links is:

Resource abbreviation	MassIVE
Resource identifier	UniProtKB accession number

Example: Q8IY92

Show all entries having a cross-reference to MassIVE.

Text format

Example: Q8IY92

DR   MassIVE; Q8IY92; -.

XML format

Example: Q8IY92

<dbReference type="MassIVE" id="Q8IY92"/>

RDF format

Example: Q8IY92

uniprot:Q8IY92
  rdfs:seeAlso <http://purl.uniprot.org/massive/Q8IY92> .
<http://purl.uniprot.org/massive/Q8IY92>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/MassIVE> .

Changes to the controlled vocabulary of human diseases

New diseases:

• Abnormal hair, joint laxity, and developmental delay
• Bleeding disorder, platelet-type 22
• Brain abnormalities, neurodegeneration, and dysosteosclerosis
• Calvarial doughnut lesions with bone fragility
• Calvarial doughnut lesions with bone fragility and spondylometaphyseal dysplasia
• Cerebellar, ocular, craniofacial, and genital syndrome
• Contractures, pterygia, and variable skeletal fusions syndrome 1B
• Deafness, autosomal recessive, 114
• Deafness, autosomal recessive, 115
• Deafness, autosomal recessive, 99
• Developmental delay with or without dysmorphic facies and autism
• Encephalopathy, acute, infection-induced, 9
• Epileptic encephalopathy, early infantile, 76
• Generalized epilepsy with febrile seizures plus 10
• Immunodeficiency 62
• Intellectual developmental disorder with severe speech and ambulation defects
• Kahn-Kahn-Katsanis syndrome
• Keipert syndrome
• Long QT syndrome 8
• Neurodevelopmental disorder with seizures and speech and walking impairment
• Paganini-Miozzo syndrome
• Paragangliomas 6
• Paragangliomas 7
• Uridine-cytidineuria

Changes in subcellular location controlled vocabulary

New subcellular locations:

• Photoreceptor inner segment membrane
• Photoreceptor outer segment membrane

Modified subcellular location:

• Exosome -> Extracellular exosome

UniRef news

Change of UniRef clustering method from CD-HIT to MMseqs2

We have switched the clustering program for UniRef90 and UniRef50 from CD-HIT to MMseqs2 (Steinegger M. and Soeding J., Nat. Commun. 9 (2018)).

The clustering algorithm remains "Greedy Incremental Clustering" with the same parameters (thanks to the MMseqs2 authors for making this available). UniRef100 was not affected.

UniProt XML news

Removal of whitespace characters in the XML amino acid sequence representations

The <sequence> elements of the UniProtKB, UniParc and UniRef XML representations formatted the amino acid sequence for historic reasons with spaces and newlines. These whitespace characters had to be removed before parsing with native XML tools. To avoid this complication we have removed all whitespace characters in the <sequence> elements, so that they contain only IUPAC amino acid codes.