Functionally constrained human proteins are less prone to mutational instability from single amino acid substitutions.

ABSTRACT: Missense mutations that disrupt protein structural stability are a common pathogenic mechanism in human genetic disease. Here, we quantify potential disruption of protein stability due to amino acid substitution and show that functionally constrained proteins are less susceptible to large mutational changes in stability. Mechanistically, this relates to greater intrinsic disorder among constrained proteins and to increased B-factors in the ordered regions of constrained proteins. This phenomenon means that constrained proteins exhibit smaller stability effects due to missense mutations, and partly explains why overtransmission of pathogenic missense variation is less prevalent in genetic disorders characterised by protein truncations. We show that the most functionally constrained proteins

SUBMITTER: May M 

PROVIDER: S-EPMC11906876 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature