Single-point mutations in disordered proteins: Linking sequence, ensemble, and function

Abstract

Mutations in genomic DNA often result in single-point missense mutations in proteins. For folded proteins, the functional effect of these missense mutations can often be understood by their impact on structure. However, missense mutations in intrinsically disordered protein regions (IDRs) remain poorly understood. In IDRs, function can depend on the structural ensemble– the collection of accessible, interchanging conformations that is encoded in their amino acid sequence. We argue that, analogously to folded proteins, single-point mutations in IDRs can alter their structural ensemble, and consequently alter their biological function. To make this argument, we first provide experimental evidence from the literature showcasing how single-point missense mutations in IDRs affect their ensemble dimensions. Then, we use genomic data from patients to show that disease-linked missense mutations occurring in IDRs can, in many cases, significantly alter IDR structural ensembles. We hope this analysis prompts further study of disease-linked, single-point mutations in IDRs. • Single point mutations in intrinsically disordered protein regions (IDRs) are poorly studied. • Multiple studies show that single-point mutations can change IDR structural ensembles. • Studies also show that a change in structural ensembles of IDRs can lead to a change in function. • Analysis of thousands of disease-linked, single-point mutations in IDRs shows that many may significantly alter structural ensembles. • We propose that at least in some of these cases, pathology can be driven by single point mutations that alter IDR structural ensemble and their subsequent function.

Topics & Concepts