Pathogenic mutations disrupt allosteric control by .

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 have been reported in patients. How exactly these mutations disrupt the catalytic activity of , and thereby lead to oncogenesis, is unknown. Here, we posit that the mechanism of pathogenesis is tied to how binding of activates for E3 ligase activity. We use atomistic molecular dynamics simulations and Markov state modeling to uncover how selects for active conformational states of . We show that the helix bundle, where binds, is allosterically coupled to the E2 interface. Furthermore, we show that 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 .