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UniProt release 2021_03

Published June 2, 2021

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 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:

Changes to the controlled vocabulary of human diseases

New diseases:

Modified diseases:

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:

Changes to keywords

New keyword:

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