Disease-Associated Mutations Disrupt Functionally Important Regions of Intrinsic Protein Disorder

Vladimir Vacic,Vladimir N Uversky,Christopher J Oldfield,Phineus R L Markwick,Xiaoyue Zhao,Lilia M Iakoucheva,Chad Haynes,Yanay Ofran

doi:10.1371/journal.pcbi.1002709

Abstract

The effects of disease mutations on protein structure and function have been extensively investigated, and many predictors of the functional impact of single amino acid substitutions are publicly available. The majority of these predictors are based on protein structure and evolutionary conservation, following the assumption that disease mutations predominantly affect folded and conserved protein regions. However, the prevalence of the intrinsically disordered proteins (IDPs) and regions (IDRs) in the human proteome together with their lack of fixed structure and low sequence conservation raise a question about the impact of disease mutations in IDRs. Here, we investigate annotated missense disease mutations and show that 21.7% of them are located within such intrinsically disordered regions. We further demonstrate that 20% of disease mutations in IDRs cause local disorder-to-order transitions, which represents a 1.7–2.7 fold increase compared to annotated polymorphisms and neutral evolutionary substitutions, respectively. Secondary structure predictions show elevated rates of transition from helices and strands into loops and vice versa in the disease mutations dataset. Disease disorder-to-order mutations also influence predicted molecular recognition features (MoRFs) more often than the control mutations. The repertoire of disorder-to-order transition mutations is limited, with five most frequent mutations (R→W, R→C, E→K, R→H, R→Q) collectively accounting for 44% of all deleterious disorder-to-order transitions. As a proof of concept, we performed accelerated molecular dynamics simulations on a deleterious disorder-to-order transition mutation of tumor protein p63 and, in agreement with our predictions, observed an increased α-helical propensity of the region harboring the mutation. Our findings highlight the importance of mutations in IDRs and refine the traditional structure-centric view of disease mutations. The results of this study offer a new perspective on the role of mutations in disease, with implications for improving predictors of the functional impact of missense mutations.

Highlights

Recent years have seen significant advancements in cataloging the genetic variation in humans and relating it to disease susceptibility
Disordered proteins do not conform to the prevailing view of deleterious mutations which equates function, structure and evolutionary conservation – intrinsically disordered regions are functional, but lack a fixed three-dimensional structure and in general have low sequence conservation
We further show that 20% of deleterious mutations in intrinsically disordered regions (IDRs) induce predicted disorder-to-order transitions

Summary

Introduction

Recent years have seen significant advancements in cataloging the genetic variation in humans and relating it to disease susceptibility. Numerous computational models that classify amino acid substitutions as damaging or benign are currently available (reviewed in [1,2,3]) The majority of these methods rely on the information from solved or modeled protein structures [4,5,6,7,8,9] and/or are based on evolutionary conservation, following the assumption that functionally important residues of proteins are conserved [10,11,12,13]. It has recently been observed that SIFT predictions have more false negatives on annotated disease mutations in disordered, solvent accessible and non-conserved regions [14]

Methods

Results

Discussion

Conclusion