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Pathogenic BRCA1 mutations disrupt allosteric control by BARD1.

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Summary

Pathogenic BRCA1 mutations disrupt cancer-linked E3 ligase activity by destabilizing its active states. Understanding how BARD1 binding selects for active BRCA1 conformations offers a strategy for developing new therapeutics.

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Area of Science:

  • Biophysics
  • Molecular Biology
  • Cancer Research

Background:

  • Pathogenic missense mutations in BRCA1 are linked to hereditary breast and ovarian cancer.
  • The exact mechanism by which these mutations disrupt BRCA1's E3 ligase activity and lead to oncogenesis remains unclear.
  • BRCA1's E3 ligase activity is activated by the binding of BARD1.

Purpose of the Study:

  • To elucidate the mechanism by which BARD1 binding activates BRCA1's E3 ligase activity.
  • To investigate how pathogenic mutations in BRCA1 affect its conformational states and E3 ligase activity.
  • To identify potential therapeutic strategies for restoring BRCA1 function.

Main Methods:

  • Atomistic molecular dynamics simulations.
  • Markov state modeling.
  • Allosteric coupling analysis.

Main Results:

  • BARD1 binding selects for 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:

  • BRCA1 pathogenesis is linked to BARD1-mediated selection of active conformational states.
  • Pathogenic mutations disrupt this process by allosterically destabilizing active states.
  • These findings provide a mechanistic basis for designing small molecule therapeutics to restore BRCA1 function.