ArticlePLoS computational biology2022
Characterization of intrinsically disordered regions in proteins informed by human genetic diversity.
Article in PLoS computational biology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 33 citations in OpenAlex.
- Reading Between the ABCs: Intrinsic Disorder and Evolutionary Dynamics of Non-Canonical Regions in ABC Transporters.International journal of molecular sciences · 2026Article
- From chromosomal protein disorder to chromatin phase separation.Epigenetics & chromatin · 2026Review
- Disordered but Different: Functional and Evolutionary Divergence of Transcription Factor Intrinsically Disordered Regions.bioRxiv : the preprint server for biology · 2026Article
- Decoding intrinsically disordered regions in biomolecular condensates.Fundamental research · 2026Review
- Generalizable and scalable protein stability prediction with rewired protein generative models.Nature communications · 2025Article
- In silico functional, structural, and pathogenicity assessment of single nucleotide polymorphisms in the human SOX9 gene.Scientific reports · 2025Article
- Missense mutations in intrinsically disordered protein regions link pathogenicity and phase separation.The Journal of biological chemistry · 2025Article
- Single-point mutations in disordered proteins: Linking sequence, ensemble, and function.Current opinion in structural biology · 2025Review
- Discordance between a deep learning model and clinical-grade variant pathogenicity classification in a rare disease cohort.NPJ genomic medicine · 2025Article
- Conservation of OFD1 Protein Motifs: Implications for Discovery of Novel Interactors and the OFD1 Function.International journal of molecular sciences · 2025Article
- In Silico Functional and Structural Analysis of Non-synonymous Single Nucleotide Polymorphisms (nsSNPs) in Human Paired Box 4 Gene.Biochemical genetics · 2024Article
- Prediction and assessment of deleterious and disease causing nonsynonymous single nucleotide polymorphisms (nsSNPs) in humanHeliyon · 2024Article
- Discordance between a deep learning model and clinical-grade variant pathogenicity classification in a rare disease cohort.medRxiv : the preprint server for health sciences · 2024Article
- In silico functional, structural and pathogenicity analysis of missense single nucleotide polymorphisms in human MCM6 gene.Scientific reports · 2024Article
- Molecular Docking of Intrinsically Disordered Proteins: Challenges and Strategies.Methods in molecular biology (Clifton, N.J.) · 2024Article
- A Comprehensive Report of Intrinsically Disordered Regions in Inherited Retinal Diseases.Genes · 2023Review
- Enrichment patterns of intrinsic disorder in proteins.Biophysical reviews · 2022Review
- Compositional Bias of Intrinsically Disordered Proteins and Regions and Their Predictions.Biomolecules · 2022Article
- Implementation of multigene panel testing for breast and ovarian cancer in South Africa: A step towards excellence in oncology for the public sector.Frontiers in oncology · 2022Article
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Authors and funding
7 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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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