ArticleMolecular bioSystems2014
Proteome-wide analysis of human disease mutations in short linear motifs: neglected players in cancer?
Article in Molecular bioSystems, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers.
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Who cites it
56 citing papers in PubMed.
- Variant characterization in the intrinsically disordered human proteome.Nature structural & molecular biology · 2026Article
- Missense mutations in intrinsically disordered protein regions link pathogenicity and phase separation.The Journal of biological chemistry · 2025Article
- Post-transcriptional control of gene expression by β-catenin: expanding the non-canonical ARMoury.Oncogene · 2025Review
- Pan-cancer analysis reveals age-associated genetic alterations in protein domains.American journal of human genetics · 2025Article
- Cell signaling inFrontiers in cellular and infection microbiology · 2025Review
- A quantitative intracellular peptide binding assay reveals recognition determinants and context dependence of short linear motifs.bioRxiv : the preprint server for biology · 2024Article
- Proteome-scale characterisation of motif-based interactome rewiring by disease mutations.Molecular systems biology · 2024Article
- Elaboration of the Homer1 recognition landscape reveals incomplete divergence of paralogous EVH1 domains.Protein science : a publication of the Protein Society · 2024Article
- Elaboration of the Homer1 Recognition Landscape Reveals Incomplete Divergence of Paralogous EVH1 Domains.bioRxiv : the preprint server for biology · 2024Article
- Fast and scalable querying of eukaryotic linear motifs with gget elm.Bioinformatics (Oxford, England) · 2024Article
- From interaction networks to interfaces, scanning intrinsically disordered regions using AlphaFold2.Nature communications · 2024Article
- ELM-the Eukaryotic Linear Motif resource-2024 update.Nucleic acids research · 2024Article
- Discovery and Characterization of Linear Motif Mediated Protein-Protein Complexes.Advances in experimental medicine and biology · 2024Article
- Intrinsically disordered proteins and conformational noise: The hypothesis a decade later.iScience · 2023Review
- The nexus between RNA-binding proteins and their effectors.Nature reviews. Genetics · 2023Review
- Review
- β-Synuclein: An Enigmatic Protein with Diverse Functionality.Biomolecules · 2022Review
- The Eukaryotic Linear Motif resource: 2022 release.Nucleic acids research · 2022Article
- Investigating the eukaryotic host-like SLiMs in microbial mimitopes and their potential as novel drug targets for treating autoimmune diseases.Frontiers in microbiology · 2022Article
- Transcription Factor Dynamics.Cold Spring Harbor perspectives in biology · 2021Review
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Authors and funding
5 authors.
Funding
Abstract
Disease mutations are traditionally thought to impair protein functionality by disrupting the folded globular structure of proteins. However, 22% of human disease mutations occur in natively unstructured segments of proteins known as intrinsically disordered regions (IDRs). This therefore implicates defective IDR functionality in various human diseases including cancer. The functionality of IDRs is partly attributable to short linear motifs (SLiMs), but it remains an open question how much defects in SLiMs contribute to human diseases. A proteome-wide comparison of the distribution of missense mutations from disease and non-disease mutation datasets revealed that, in IDRs, disease mutations are more likely to occur within SLiMs than neutral missense mutations. Moreover, compared to neutral missense mutations, disease mutations more frequently impact functionally important residues of SLiMs, cause changes in the physicochemical properties of SLiMs, and disrupt more SLiM-mediated interactions. Analysis of these mutations resulted in a comprehensive list of experimentally validated or predicted SLiMs disrupted in disease. Furthermore, this in-depth analysis suggests that 'prostate cancer pathway' is particularly enriched for proteins with disease-related SLiMs. The contribution of mutations in SLiMs to disease may currently appear small when compared to mutations in globular domains. However, our analysis of mutations in predicted SLiMs suggests that this contribution might be more substantial. Therefore, when analysing the functional impact of mutations on proteins, SLiMs in proteins should not be neglected. Our results suggest that an increased focus on SLiMs in the coming decades will improve our understanding of human diseases and aid in the development of targeted treatments.
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