Key result
Pathogenic BRCA1 mutations destabilize active E3 ligase conformational states while hyperactive mutations increase their likelihood.
Why the study?
How pathogenic mutations in the N-terminal domain of BRCA1 disrupt its catalytic activity and lead to oncogenesis in hereditary breast and ovarian cancer was unknown.
Pathogenic BRCA1 mutations disrupt allosteric control by BARD1, destabilizing active conformational states required for E3 ligase activity.
Answers are grounded in this paper and cite their sources.
May refine BRCA1 variant models in preclinical systems; leaves open human translation and therapeutic targeting.
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 cancer, 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 active conformational states of BRCA1 . We show that the helix bundle, where BARD1 binds, is allosterically coupled to the E2 interface. Furthermore, we show that BARD1 selects for conformational states that are pre-organized for E3 activity. Lastly, we show that pathogenic mutations allosterically destabilize active states, whereas hyperactive mutations constitutively increase their likelihood. These results provide a concrete strategy supported by mechanistic insight for the design of restorative small molecules targeting BRCA1 .
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Bhattacharjee et al. (2025) studied Hereditary breast and ovarian cancer. Pathogenic BRCA1 mutations was evaluated on Conformational states and E3 ligase activity. Pathogenic BRCA1 mutations allosterically destabilize active conformational states pre-organized for E3 ligase activity, whereas hyperactive mutations constitutively increase their likelihood.
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