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首页> 外文期刊>Journal of Molecular Biology >Congenital Cataract-Causing Mutation G129C in gamma C-Crystallin Promotes the Accumulation of Two Distinct Unfolding Intermediates That Form Highly Toxic Aggregates
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Congenital Cataract-Causing Mutation G129C in gamma C-Crystallin Promotes the Accumulation of Two Distinct Unfolding Intermediates That Form Highly Toxic Aggregates

机译：导致先天性白内障致突变的G129C晶体C129C促进形成高毒性聚集体的两个不同的展开中间体的积累

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Cataract is a lens opacification disease prevalent worldwide. Cataract-causing mutations in crystallins generally lead to the formation of light-scattering particles in the lens. However, it remains unclear for the detailed structural and pathological mechanisms of most mutations. In this study, we showed that the G129C mutation in gamma C-crystallin, which is associated with autosomal dominant congenital nuclear cataract, perturbed the unfolding process by promoting the accumulation of two distinct aggregation-prone intermediates under mild denaturing conditions. The abnormally accumulated intermediates escaped from the chaperone-like function of alpha A-crystallin during refolding. Molecular dynamics simulations indicated that the mutation altered domain pairing geometry and allowed the penetration of extra solvent molecules into the domain binding interface, thereby weakening domain binding energy. Under mild denaturation conditions, the increased domain movements may facilitate the formation of non-native oligomers via domain swapping, which further assembled into amyloid-like fibrils. The intermediate that appeared at 1.6 M guanidine hydrochloride was more compact and less aggregatory than the one populated at 0.9 M guanidine hydrochloride, which was caused by the increased solvation of acidic residues in the ion-pairing network via the competitive binding of guanidinium ions. More importantly, both the amyloid-like fibrils preformed in vitro and intracellular aggresomes formed by exogenously overexpressed mutant proteins significantly inhibited cell proliferation and induced cell death. The combined data from spectroscopic, structural and cellular studies strongly suggest that both the formation of light-scattering aggregates and the toxic effects of the aggregates may contribute to the onset and development of cataract. (C) 2015 Elsevier Ltd. All rights reserved.
机译：白内障是一种在世界范围内普遍存在的晶状体混浊疾病。晶状体中引起白内障的突变通常导致晶状体中光散射粒子的形成。然而，对于大多数突变的详细结构和病理机制尚不清楚。在这项研究中，我们表明，γC-晶状体蛋白中的G129C突变与常染色体显性先天性白内障有关，通过在温和的变性条件下促进两种不同的易于聚集的中间体的积累，扰乱了展开过程。异常积累的中间体在重折叠过程中逃脱了αA-晶状蛋白的分子伴侣样功能。分子动力学模拟表明，该突变改变了结构域配对的几何结构，并允许额外的溶剂分子渗透到结构域结合界面中，从而削弱了结构域结合能。在温和的变性条件下，增加的结构域移动可能有助于通过结构域交换形成非天然寡聚物，后者进一步组装成淀粉样蛋白原纤维。在1.6 M盐酸胍中出现的中间体比在0.9 M盐酸胍中存在的中间体更致密且不易聚集，这是由于通过胍离子的竞争性结合导致离子对网络中酸性残基的溶剂化增加。更重要的是，体外形成的淀粉样蛋白原纤维和外源过度表达的突变蛋白形成的细胞内聚集体均显着抑制细胞增殖并诱导细胞死亡。来自光谱，结构和细胞研究的综合数据强烈表明，光散射聚集体的形成和聚集体的毒性作用都可能有助于白内障的发作和发展。 （C）2015 Elsevier Ltd.保留所有权利。

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