The Eukaryotic Linear Motif resource: 2022 release

Kumar, M. Ravi; Michael, Sushama; Alvarado-Valverde, Jesús; Mészáros, Bálint; Sámano-Sánchez, Hugo; Zeke, András; Dobson, László; Lázár, Tamás; Örd, Mihkel; Nagpal, Anurag; Farahi, Nazanin; Käser, Melanie; Kraleti, Ramya; Davey, Norman E.; Pancsa, Rita; Chemes, Lucía B.; Gibson, Toby J.

doi:10.1093/nar/gkab975

Cited by 214 publications

(231 citation statements)

References 95 publications

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“…the abundance of short linear motifs and PTM sites (“modified residues,” “cross-links,” “lipidations,” etc., Figs 1 and S1 – S4 ), consistently with IDRs’ role in cell signaling and molecular regulation [ 17 , 19 , 54 ]. Further characterization of the UniProt feature “motif” was performed using the Eukaryotic Linear Motif (ELM) resource [ 55 , 56 ], that organizes experimentally validated short linear motifs into types based on their functions. This showed that 41% and 18% of the motifs overlapping with IDRs in our dataset are ligand sites (LIG), which mediate binding of the ligand protein to its interaction partner, and subcellular targeting sites (TRG), respectively ( S6A Fig and S8 Table ).…”

Section: Discussionmentioning

confidence: 99%

Characterization of intrinsically disordered regions in proteins informed by human genetic diversity

et al. 2022

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All proteomes contain both proteins and polypeptide segments that don’t form a defined three-dimensional structure yet are biologically active—called intrinsically disordered proteins and regions (IDPs and IDRs). Most of these IDPs/IDRs lack useful functional annotation limiting our understanding of their importance for organism fitness. Here we characterized IDRs using protein sequence annotations of functional sites and regions available in the UniProt knowledgebase (“UniProt features”: active site, ligand-binding pocket, regions mediating protein-protein interactions, etc.). By measuring the statistical enrichment of twenty-five UniProt features in 981 IDRs of 561 human proteins, we identified eight features that are commonly located in IDRs. We then collected the genetic variant data from the general population and patient-based databases and evaluated the prevalence of population and pathogenic variations in IDPs/IDRs. We observed that some IDRs tolerate 2 to 12-times more single amino acid-substituting missense mutations than synonymous changes in the general population. However, we also found that 37% of all germline pathogenic mutations are located in disordered regions of 96 proteins. Based on the observed-to-expected frequency of mutations, we categorized 34 IDRs in 20 proteins (DDX3X, KIT, RB1, etc.) as intolerant to mutation. Finally, using statistical analysis and a machine learning approach, we demonstrate that mutation-intolerant IDRs carry a distinct signature of functional features. Our study presents a novel approach to assign functional importance to IDRs by leveraging the wealth of available genetic data, which will aid in a deeper understating of the role of IDRs in biological processes and disease mechanisms.

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Section: Discussionmentioning

confidence: 99%

Characterization of intrinsically disordered regions in proteins informed by human genetic diversity

et al. 2022

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“…FuzDB has a new interface and expanded links out to databases covering protein structure, function and involvement in phase separation. Short linear interaction motifs are particularly common in intrinsically disordered regions and the database for such motifs in eukaryotes, ELM, contributes an Update paper ( 44 ). Among highlighted examples of newly catalogued motifs, the authors use a KEGG ( 45 ) image of endocytosis pathways to emphasise the ubiquity of motif-mediated interactions in the process and illustrate the multiple points at which diverse viruses hijack pathway components.…”

Section: New and Updated Databasesmentioning

confidence: 99%

The 2022Nucleic Acids Researchdatabase issue and the online molecular biology database collection

Rigden

Fernández

2021

Nucleic Acids Research

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The 2022 Nucleic Acids Research Database Issue contains 185 papers, including 87 papers reporting on new databases and 85 updates from resources previously published in the Issue. Thirteen additional manuscripts provide updates on databases most recently published elsewhere. Seven new databases focus specifically on COVID-19 and SARS-CoV-2, including SCoV2-MD, the first of the Issue's Breakthrough Articles. Major nucleic acid databases reporting updates include MODOMICS, JASPAR and miRTarBase. The AlphaFold Protein Structure Database, described in the second Breakthrough Article, is the stand-out in the protein section, where the Human Proteoform Atlas and GproteinDb are other notable new arrivals. Updates from DisProt, FuzDB and ELM comprehensively cover disordered proteins. Under the metabolism and signalling section Reactome, ConsensusPathDB, HMDB and CAZy are major returning resources. In microbial and viral genomes taxonomy and systematics are well covered by LPSN, TYGS and GTDB. Genomics resources include Ensembl, Ensembl Genomes and UCSC Genome Browser. Major returning pharmacology resource names include the IUPHAR/BPS guide and the Therapeutic Target Database. New plant databases include PlantGSAD for gene lists and qPTMplants for post-translational modifications. The entire Database Issue is freely available online on the Nucleic Acids Research website (https://academic.oup.com/nar). Our latest update to the NAR online Molecular Biology Database Collection brings the total number of entries to 1645. Following last year's major cleanup, we have updated 317 entries, listing 89 new resources and trimming 80 discontinued URLs. The current release is available at http://www.oxfordjournals.org/nar/database/c/.

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“…For many protein domains beyond EVH1, degenerate SLiMs have been cataloged in the Eukaryotic Linear Motif (ELM) database to describe their interaction preferences ( Kumar et al, 2022 ). The ELM listing implies that there is a relatively simple recognition code for many key domain interactions.…”

Section: Discussionmentioning

confidence: 99%

Native proline-rich motifs exploit sequence context to target actin-remodeling Ena/VASP protein ENAH

Hwang

Parker

Hill

et al. 2022

eLife

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The human proteome is replete with short linear motifs (SLiMs) of four to six residues that are critical for protein-protein interactions, yet the importance of the sequence surrounding such motifs is underexplored. We devised a proteomic screen to examine the influence of SLiM sequence context on protein-protein interactions. Focusing on the EVH1 domain of human ENAH, an actin regulator that is highly expressed in invasive cancers, we screened 36-residue proteome-derived peptides and discovered new interaction partners of ENAH and diverse mechanisms by which context influences binding. A pocket on the ENAH EVH1 domain that has diverged from other Ena/VASP paralogs recognizes extended SLiMs and favors motif-flanking proline residues. Many high-affinity ENAH binders that contain two proline-rich SLiMs use a noncanonical site on the EVH1 domain for binding and display a thermodynamic signature consistent with the two-motif chain engaging a single domain. We also found that photoreceptor cilium actin regulator (PCARE) uses an extended 23-residue region to obtain a higher affinity than any known ENAH EVH1-binding motif. Our screen provides a way to uncover the effects of proteomic context on motif-mediated binding, revealing diverse mechanisms of control over EVH1 interactions and establishing that SLiMs can’t be fully understood outside of their native context.

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The Eukaryotic Linear Motif resource: 2022 release

Cited by 214 publications

References 95 publications

Characterization of intrinsically disordered regions in proteins informed by human genetic diversity

Characterization of intrinsically disordered regions in proteins informed by human genetic diversity

The 2022Nucleic Acids Researchdatabase issue and the online molecular biology database collection

Native proline-rich motifs exploit sequence context to target actin-remodeling Ena/VASP protein ENAH

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