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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Distinct amyloid fibril structures formed by ALS-causing SOD1 mutants G93A and D101N.
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.
期刊介绍：
EMBO Reports is a scientific journal that specializes in publishing research articles in the fields of molecular biology, cell biology, and developmental biology. The journal is known for its commitment to publishing high-quality, impactful research that provides novel physiological and functional insights. These insights are expected to be supported by robust evidence, with independent lines of inquiry validating the findings.
The journal's scope includes both long and short-format papers, catering to different types of research contributions. It values studies that:
Communicate major findings: Articles that report significant discoveries or advancements in the understanding of biological processes at the molecular, cellular, and developmental levels.
Confirm important findings: Research that validates or supports existing knowledge in the field, reinforcing the reliability of previous studies.
Refute prominent claims: Studies that challenge or disprove widely accepted ideas or hypotheses in the biosciences, contributing to the correction and evolution of scientific understanding.
Present null data: Papers that report negative results or findings that do not support a particular hypothesis, which are crucial for the scientific process as they help to refine or redirect research efforts.
EMBO Reports is dedicated to maintaining high standards of scientific rigor and integrity, ensuring that the research it publishes contributes meaningfully to the advancement of knowledge in the life sciences. By covering a broad spectrum of topics and encouraging the publication of both positive and negative results, the journal plays a vital role in promoting a comprehensive and balanced view of scientific inquiry.
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