Document Detail

Disease mutations in disordered regions--exception to the rule?
MedLine Citation:
PMID:  22080206     Owner:  NLM     Status:  MEDLINE    
Intrinsically disordered proteins (IDPs) have been implicated in a number of human diseases, including cancer, diabetes, neurodegenerative and cardiovascular disorders. Although for some of these conditions molecular mechanisms are now better understood, the big picture connecting distinct structural properties and functional repertoire of IDPs to pathogenesis and disease progression is still incomplete. Recent studies suggest that signaling and regulatory roles carried out by IDPs require them to be tightly regulated, and that altered IDP abundance may lead to disease. Here, we propose another link between IDPs and disease that takes into account disease-associated missense mutations located in the intrinsically disordered regions. We argue that such mutations are more prevalent and have larger functional impact than previously thought. In addition, we demonstrate that deleterious amino acid substitutions that cause disorder-to-order transitions are particularly enriched among disease mutations compared to neutral polymorphisms. Finally, we discuss potential differences in functional outcomes between disease mutations in ordered and disordered regions, and challenge the conventional structure-centric view of missense mutations.
Vladimir Vacic; Lilia M Iakoucheva
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.; Review     Date:  2011-11-14
Journal Detail:
Title:  Molecular bioSystems     Volume:  8     ISSN:  1742-2051     ISO Abbreviation:  Mol Biosyst     Publication Date:  2012 Jan 
Date Detail:
Created Date:  2011-12-02     Completed Date:  2012-03-20     Revised Date:  2014-09-20    
Medline Journal Info:
Nlm Unique ID:  101251620     Medline TA:  Mol Biosyst     Country:  England    
Other Details:
Languages:  eng     Pagination:  27-32     Citation Subset:  IM    
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MeSH Terms
Databases, Protein
Disease / genetics*
Mutation / genetics*
Protein Conformation
Protein Folding*
Proteins / chemistry*,  genetics*,  metabolism
Grant Support
R01 HD065288/HD/NICHD NIH HHS; R01 HD065288/HD/NICHD NIH HHS; R01 HD065288-02/HD/NICHD NIH HHS; R01 MH091350/MH/NIMH NIH HHS; R01 MH091350/MH/NIMH NIH HHS; R01 MH091350-02/MH/NIMH NIH HHS
Reg. No./Substance:

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