Human γD-crystallin (HγD) is an abundant and highly stable two-domain protein in the core region of the eye lens. Destabilizing mutations and post-translational modifications in this protein are linked to onset of aggregation that causes cataract disease (lens turbidity). Wild-type HγD greatly accelerates aggregation of the cataract-related W42Q variant, without itself aggregating. The mechanism of this “inverse prion” catalysis of aggregation remained unknown. Here we provide evidence that an early unfolding intermediate with an opened domain interface enables transient dimerization of the C-terminal domains of wild-type and mutant, or mutant and mutant, HγD molecules, which deprives the mutant’s N-terminal domain of intramolecular stabilization by the native domain interface and thus accelerates its misfolding to a distinct, aggregation-prone intermediate. A detailed kinetic model predicts universal power-law scaling relationships for lag time and rate of the resulting aggregation, which are in excellent agreement with the data. The mechanism reported here, which we term interface stealing, can be generalized to explain how common domain-domain interactions can have surprising consequences, such as conformational catalysis of unfolding, in multidomain proteins.