A cataract-causing Y204X mutation of CRYβB1 promotes C-terminal degradation and higher-order oligomerization

Crystallin (Cry) proteins are a class of main structural proteins of vertebrate eye lens, and their solubility and stability directly determine transparency and refractive power of the lens. Mutation in genes that encode for these Cry proteins is the common cause for congenital cataract. Despite extensive studies, the pathogenic and molecular mechanisms remain unclear. In this study, we identified a novel mutation in CRYBB1 from a congenital cataract family, and demonstrated that this mutation led to an earlier termination of protein translation, resulting in a 49-residue truncation at the CRY{beta}B1 C-terminus. This mutant is susceptible to proteolysis and allows us to determine a 1.2- [A] resolution crystal structure of CRY{beta}B1 without the entire C-terminal domain. In this crystal lattice, two N-terminal domain monomers form a dimer that structurally resembles a wild-type (WT) monomer, but with different surface characteristics. Biochemical analyses suggest that this mutant is significantly more liable to aggregate and degrade, when compared to WT CRY{beta}B1. All our results provide an insight into the mechanism regarding how a mutant Cry contributes to the development of congenital cataract possibly through alteration of inter-protein interactions that result in the opacity of eye lens.