Department of Agricultural Biotechnology, and Research Institute of Agriculture and Life Sciences, CALS, Seoul National University, Seoul, 08826, Republic of Korea.
Department of Molecular Biology, College of Natural Science, Pusan National University, Busan, 46241, Republic of Korea.
Commun Biol. 2022 Oct 12;5(1):1085. doi: 10.1038/s42003-022-04017-0.
Eukaryotic Cu, Zn-superoxide dismutase (SOD1) is primarily responsible for cytotoxic filament formation in amyotrophic lateral sclerosis (ALS) neurons. Two cysteine residues in SOD1 form an intramolecular disulfide bond. This study aims to explore the molecular mechanism of SOD1 filament formation by cysteine overoxidation in sporadic ALS (sALS). In this study, we determined the crystal structure of the double mutant (C57D/C146D) SOD1 that mimics the overoxidation of the disulfide-forming cysteine residues. The structure revealed the open and relaxed conformation of loop IV containing the mutated Asp57. The double mutant SOD1 produced more contagious filaments than wild-type protein, promoting filament formation of the wild-type SOD1 proteins. Importantly, we further found that HOCl treatment to the wild-type SOD1 proteins facilitated their filament formation. We propose a feasible mechanism for SOD1 filament formation in ALS from the wild-type SOD1, suggesting that overoxidized SOD1 is a triggering factor of sALS. Our findings extend our understanding of other neurodegenerative disorders associated with ROS stresses at the molecular level.
真核生物铜锌-超氧化物歧化酶（SOD1）主要负责肌萎缩侧索硬化症（ALS）神经元中的细胞毒性丝状体形成。SOD1 中的两个半胱氨酸残基形成分子内二硫键。本研究旨在通过对散发性 ALS（sALS）中半胱氨酸过氧化来探索 SOD1 丝状体形成的分子机制。在这项研究中，我们测定了模拟二硫键形成半胱氨酸残基过氧化的双突变体（C57D/C146D）SOD1 的晶体结构。该结构揭示了含有突变天冬氨酸 57 的环 IV 的开放和松弛构象。与野生型蛋白相比，双突变体 SOD1 产生了更多传染性丝状体，促进了野生型 SOD1 蛋白的丝状体形成。重要的是，我们进一步发现 HOCl 处理野生型 SOD1 蛋白促进了其丝状体的形成。我们从野生型 SOD1 中提出了一个可行的 ALS 中 SOD1 丝状体形成机制，表明过氧化 SOD1 是 sALS 的一个触发因素。我们的发现从分子水平上扩展了对与 ROS 应激相关的其他神经退行性疾病的理解。
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