How post-translational modifications alter the structures and interactions of proteins is of great interest for understanding proteomic changes during aging and disease. Oxidative modifications of the long-lived cysteine-rich lens γ-crystallins are strongly associated with their aggregation into light-scattering structures that result in cataracts - the leading cause of age-related vision loss. How oxidation leads to aggregation is not well understood. Our previous computational and experimental work showed that formation of a particular non-native intramolecular disulfide bond in cataract-associated W42Q/R human γD-crystallin variants trapped a partially unfolded intermediate state prone to aggregation. Surprisingly, it also revealed that the wild-type protein was able to specifically promote aggregation of these variants without itself aggregating. The search for a biochemical mechanism behind this unprecedented “inverse- prion” interaction has now revealed that human γD-crystallin exhibits oxidoreductase activity. This activity depended on formation of a specific internal disulfide bond, which we mapped by LC/MS/MS and by comprehensive Cys mutagenesis. All-atom Monte-Carlo simulations with a statistical potential revealed conformational strain upon formation of this disulfide, which was confirmed by differential scanning flourometry. Disulfide exchange occurred among purified γD-crystallin molecules in solution. Both the Cys-oxidized (disulfide-bonded) wild-type protein and the destabilized (Trp-oxidation mimicking) W42Q variant were highly soluble at physiological temperature and pH. When the two were mixed, however, the disulfide bond transferred from the WT to the mutant. Once oxidized, the mutant became aggregation-prone, its insolubilization helping drive the disulfide transfer. Destabilized or damaged γ- crystallins may act as oxidation sinks in the lens, forming light-scattering aggregates as a consequence. There is evidence that human γD-crystallin's newly found oxidoreductase activity is enzymatically regulated in vivo.