An Internal Disulfide Locks a Misfolded Aggregation-Prone Intermediate in Cataract-Linked Mutants of Human Gamma-D Crystallin

A large class of non-amyloid protein aggregates are considered amorphous; in most cases little is known about detailed mechanisms, if any, that underlie these aggregation phenomena. Amorphous aggregation of the γ-crystallins in the eye lens causes a widespread disease of aging, cataract. We combined simulations and experiments to study the mechanism of aggregation of two γD-crystallin mutants, the congenital cataract mutation W42R and the mimic of age-related oxidative damage W42Q. The two mutants had highly similar properties.