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

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.