Distinct amyloid fibril structures formed by ALS-causing SOD1 mutants G93A and D101N.

IF 6.2 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

EMBO Reports Pub Date : 2025-10-01 Epub Date: 2025-08-26 DOI:10.1038/s44319-025-00557-8

Mu-Ya Zhang, Yeyang Ma, Li-Qiang Wang, Wencheng Xia, Xiang-Ning Li, Kun Zhao, Jie Chen, Dan Li, Liangyu Zou, Zhengzhi Wang, Cong Liu, Yi Liang

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引用次数: 0

Abstract

Two hundred eight genetic mutations in SOD1 have been linked to amyotrophic lateral sclerosis (ALS). Of these, the G93A and D101N variants maintain much of their physiological function, closely resembling that of wild-type SOD1, and the SOD1-G93A transgenic mouse is the most extensively used mouse line in the study of ALS. In this study, we report two cryo-EM structures of amyloid fibrils formed by G93A and D101N mutants of SOD1 protein. These mutations give rise to amyloid fibrils with distinct structures compared to native SOD1 fibrils. The fibril core displays a serpentine configuration featuring four β-strands, held together by two hydrophobic cavities and a salt bridge between Arg143 and Asp96 in the G93A fibril, and by a hydrophobic cavity and a salt bridge between Arg143 and Asp132 in the D101N fibril, demonstrating unique structural features for each mutant. Moreover, our results show that G93A fibrils are significantly more toxic than those formed by D101N, which do not show a marked increase in toxicity compared to wild-type SOD1 fibrils. This study sheds light on the structural mechanisms through which SOD1 mutants aggregate and induce cytotoxicity in ALS.

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引起als的SOD1突变体G93A和D101N形成不同的淀粉样蛋白纤维结构。

有228个SOD1基因突变与肌萎缩侧索硬化症（ALS）有关。其中，G93A和D101N变体保持了其大部分生理功能，与野生型SOD1非常相似，SOD1-G93A转基因小鼠是ALS研究中使用最广泛的小鼠系。在这项研究中，我们报道了SOD1蛋白的G93A和D101N突变体形成的淀粉样蛋白原纤维的两种低温电镜结构。与天然SOD1原纤维相比，这些突变产生具有不同结构的淀粉样原纤维。原纤维核心呈蛇形结构，具有4条β-链，由G93A原纤维中Arg143和Asp96之间的两个疏水空腔和盐桥连接在一起，D101N原纤维中Arg143和Asp132之间的疏水空腔和盐桥连接在一起，显示出每个突变体的独特结构特征。此外，我们的研究结果表明，G93A原纤维的毒性明显高于D101N形成的原纤维，而D101N形成的原纤维的毒性与野生型SOD1原纤维相比没有明显增加。这项研究揭示了SOD1突变体聚集并诱导ALS细胞毒性的结构机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

EMBO Reports 生物-生化与分子生物学

CiteScore

11.20

自引率

1.30%

发文量

267

审稿时长

1 months

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