Hill Jake A, Nyathi Yvonne, Horrell Sam, von Stetten David, Axford Danny, Owen Robin L, Beddard Godfrey S, Pearson Arwen R, Ginn Helen M, Yorke Briony A
School of Chemistry and Biosciences, University of Bradford, Richmond Road, Bradford, BD7 1DP, United Kingdom.
School of Chemistry, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, United Kingdom.
Commun Chem. 2024 Apr 10;7(1):81. doi: 10.1038/s42004-024-01163-w.
Human gamma-D crystallin (HGD) is a major constituent of the eye lens. Aggregation of HGD contributes to cataract formation, the leading cause of blindness worldwide. It is unique in its longevity, maintaining its folded and soluble state for 50-60 years. One outstanding question is the structural basis of this longevity despite oxidative aging and environmental stressors including ultraviolet radiation (UV). Here we present crystallographic structures evidencing a UV-induced crystallin redox switch mechanism. The room-temperature serial synchrotron crystallographic (SSX) structure of freshly prepared crystallin mutant (R36S) shows no post-translational modifications. After aging for nine months in the absence of light, a thiol-adduct (dithiothreitol) modifying surface cysteines is observed by low-dose SSX. This is shown to be UV-labile in an acutely light-exposed structure. This suggests a mechanism by which a major source of crystallin damage, UV, may also act as a rescuing factor in a finely balanced redox system.
人γ-D晶状体蛋白（HGD）是眼球晶状体的主要成分。HGD的聚集会导致白内障形成，而白内障是全球失明的主要原因。它在寿命方面具有独特性，能在50至60年的时间里保持折叠和可溶状态。一个突出的问题是，尽管存在氧化衰老和包括紫外线辐射（UV）在内的环境应激因素，其长寿的结构基础是什么。在此，我们展示了晶体学结构，证明了一种紫外线诱导的晶状体蛋白氧化还原开关机制。新制备的晶状体蛋白突变体（R36S）的室温串行同步加速器晶体学（SSX）结构未显示出翻译后修饰。在无光条件下老化九个月后，通过低剂量SSX观察到一种修饰表面半胱氨酸的硫醇加合物（二硫苏糖醇）。在急性光照结构中，这种加合物显示对紫外线不稳定。这表明一种机制，即晶状体蛋白损伤的主要来源紫外线，在一个精细平衡的氧化还原系统中也可能充当拯救因子。
