Pathogenic BRCA1 Mutations Disrupt Allosteric Control by BARD1

Area of Science:

• Biophysics
• Molecular Biology
• Computational Biology

Background:

• Pathogenic mutations in BRCA1 are linked to hereditary breast and ovarian cancers.
• The precise mechanism by which these mutations disrupt BRCA1 function and lead to oncogenesis remains unclear.
• BRCA1's E3 ligase activity is regulated by binding to BARD1.

Purpose of the Study:

• To investigate the allosteric mechanisms by which BARD1 binding activates BRCA1 E3 ligase activity.
• To elucidate how pathogenic mutations in BRCA1 perturb these activation mechanisms.
• To provide mechanistic insights for designing therapeutics targeting BRCA1.

Main Methods:

• Atomistic molecular dynamics simulations.
• Markov state modeling.
• Analysis of allosteric coupling between the BARD1 binding site and the E2 interface.

Main Results:

• BARD1 binding selects for and stabilizes active conformational states of BRCA1.
• The BARD1 binding site (helix bundle) is allosterically coupled to the E2 interface.
• Pathogenic mutations destabilize these active states, while hyperactive mutations increase their likelihood.

Conclusions:

• BARD1-mediated activation of BRCA1 is a conformational selection process.
• Pathogenic BRCA1 mutations exert their effect by allosterically disrupting these active conformations.
• These findings offer a mechanistic basis for developing small molecule therapeutics to restore BRCA1 function.