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

Ahmed, Shehab S, Rifat, Zaara T, Lohia, Ruchi, Campbell, Arthur J, Dunker, A Keith, Rahman, M Sohel, Iqbal, Sumaiya (March 2022) Characterization of intrinsically disordered regions in proteins informed by human genetic diversity. PLoS Computational Biology, 18 (3). e1009911. ISSN 1553-734X

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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.

Item Type:	Paper
Subjects:	bioinformatics bioinformatics > genomics and proteomics > Mapping and Rendering > DNA Structure Rendering bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > Mapping and Rendering bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification bioinformatics > genomics and proteomics > genetics & nucleic acid processing > genomes bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein structure rendering
CSHL Authors:	Lohia, Ruchi
Communities:	CSHL labs > Gillis Lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	11 March 2022
Date Deposited:	07 Apr 2022 14:32
Last Modified:	11 Jan 2024 15:28
PMCID:	PMC8942211
URI:	https://repository.cshl.edu/id/eprint/40572

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