Pathogenic <i>BRCA1</i> Mutations Disrupt Allosteric Control by <i>BARD1</i>.

ABSTRACT: Mechanistic insight into biophysical perturbations caused by pathogenic missense mutations is highly valuable information for the rational design of therapeutics. For hereditary breast and ovarian cancers, multiple pathogenic mutations in the N-terminal domain of BRCA1 have been reported in patients. How exactly these mutations disrupt the catalytic activity of BRCA1, and thereby lead to oncogenesis, is unknown. Here, we posit that the mechanism of pathogenesis is tied to how binding of BARD1 activates BRCA1 for E3 ligase activity. We use atomistic molecular dynamics simulations and Markov state modeling to uncover how BARD1 selects for the active conformational states of BRCA1. We show that the helix bundle, where BARD1 binds, is allosteric

SUBMITTER: Bhattacharjee A 

PROVIDER: S-EPMC12362357 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature