Issue 10, 2014

Proteome-wide analysis of human disease mutations in short linear motifs: neglected players in cancer?

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.

Graphical abstract: Proteome-wide analysis of human disease mutations in short linear motifs: neglected players in cancer?

Supplementary files

Article information

Article type
Paper
Submitted
13 May 2014
Accepted
11 Jul 2014
First published
14 Jul 2014
This article is Open Access
Creative Commons BY license

Mol. BioSyst., 2014,10, 2626-2642

Author version available

Proteome-wide analysis of human disease mutations in short linear motifs: neglected players in cancer?

B. Uyar, R. J. Weatheritt, H. Dinkel, N. E. Davey and T. J. Gibson, Mol. BioSyst., 2014, 10, 2626 DOI: 10.1039/C4MB00290C

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