Research School of Chemistry, The Australian National University, Acton, ACT 2601, Australia.
Research School of Chemistry, The Australian National University, Acton, ACT 2601, Australia.
J Mol Biol. 2019 Feb 1;431(3):483-497. doi: 10.1016/j.jmb.2018.12.005. Epub 2018 Dec 13.
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 cataract. 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 γS-crystallin that was obtained via oxidation of C24. The γS-crystallin dimer is stable at glutathione concentrations comparable to those in aged and cataractous lenses. Moreover, dimerization of γS-crystallin significantly increases the protein's propensity to form large insoluble aggregates owing to non-cooperative domain unfolding, as is 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.
眼睛晶状体中的还原环境随年龄的增长而减弱，导致显著的氧化应激。晶状体蛋白的氧化是导致其不稳定和有害聚集的主要原因，这种聚集会散射可见光，影响视力，并最终导致白内障。然而，氧化诱导聚集的分子基础尚不清楚。我们使用 X 射线晶体学和小角 X 射线散射技术，描述了通过 C24 氧化获得的人 γS-晶体蛋白的二硫键连接二聚体的结构。γS-晶体蛋白二聚体在与年老和白内障晶状体中相当的谷胱甘肽浓度下稳定。此外，由于非协同结构域展开，γS-晶体蛋白的二聚化显著增加了蛋白质形成大的不溶性聚集体的倾向，这在与早发性白内障相关的晶体蛋白变体中观察到。这些发现提供了关于晶体蛋白的氧化修饰如何导致白内障的见解，并暗示早发性和年龄相关性疾病具有相似的发展途径。
