Dynamic coupling of residues within proteins as a mechanistic foundation of many enigmatic pathogenic missense variants.

ABSTRACT: Many pathogenic missense mutations are found in protein positions that are neither well-conserved nor fall in any known functional domains. Consequently, we lack any mechanistic underpinning of dysfunction caused by such mutations. We explored the disruption of allosteric dynamic coupling between these positions and the known functional sites as a possible mechanism for pathogenesis. In this study, we present an analysis of 591 pathogenic missense variants in 144 human enzymes that suggests that allosteric dynamic coupling of mutated positions with known active sites is a plausible biophysical mechanism and evidence of their functional importance. We illustrate this mechanism in a case study of β-Glucocerebrosidase (GCase) in which a vast majority of 94 sites harboring Gaucher disease-asso

SUBMITTER: Ose NJ 

PROVIDER: S-EPMC9017885 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature