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Publication Abstract from PubMed

The reducing environment in the eye lens diminishes with age, leading to significant oxidative stress. Oxidation of lens crystallin proteins is the major contributor to their destabilization and deleterious aggregation that scatters visible light, obscures vision and ultimately leads to cataracts. However, the molecular basis for oxidation-induced aggregation is unknown. Using X-ray crystallography and small angle X-ray scattering, we describe the structure of a disulfide-linked dimer of human gammaS-crystallin that was obtained via oxidation of C24. We show that the gammaS-crystallin dimer is stable at glutathione concentrations comparable to those in aged and cataractous lenses. Moreover, dimerization of gammaS-crystallin significantly increases the protein's propensity to form large insoluble aggregates owing to non-cooperative domain unfolding, as observed in crystallin variants associated with early-onset cataract. These findings provide insight into how oxidative modification of crystallins contributes to cataract and imply that early-onset and age-related forms of the disease share comparable development pathways.

The structure and stability of the disulfide-linked gammaS-crystallin dimer provide insight into oxidation products associated with lens cataract formation.,Thorn DC, Grosas AB, Mabbitt PD, Ray NJ, Jackson CJ, Carver JA J Mol Biol. 2018 Dec 12. pii: S0022-2836(18)31273-7. doi:, 10.1016/j.jmb.2018.12.005. PMID:30552875^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.