Unveiling the double-edged sword: SOD1 trimers possess tissue-selective toxicity and bind septin-7 in motor neuron-like cells

IF 4.4 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Structure Pub Date : 2024-08-28 DOI:10.1016/j.str.2024.08.002

Esther Sue Choi, Brianna Hnath, Congzhou Mike Sha, Nikolay V. Dokholyan

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Abstract

Misfolded species of superoxide dismutase 1 (SOD1) are associated with increased death in amyotrophic lateral sclerosis (ALS) models compared to insoluble protein aggregates. The mechanism by which structurally independent SOD1 trimers cause cellular toxicity is unknown but may drive disease pathology. Here, we uncovered the SOD1 trimer interactome—a map of potential tissue-selective protein-binding partners in the brain, spinal cord, and skeletal muscle. We identified binding partners and key pathways associated with SOD1 trimers and found that trimers may affect normal cellular functions such as dendritic spine morphogenesis and synaptic function in the central nervous system and cellular metabolism in skeletal muscle. We discovered SOD1 trimer-selective enrichment of genes. We performed detailed computational and biochemical characterization of SOD1 trimer protein binding for septin-7. Our investigation highlights key proteins and pathways within distinct tissues, revealing a plausible intersection of genetic and pathophysiological mechanisms in ALS through interactions involving SOD1 trimers.

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揭开双刃剑的面纱：SOD1 三聚体具有组织选择性毒性，并能与运动神经元样细胞中的 septin-7 结合

在肌萎缩性脊髓侧索硬化症（ALS）模型中，与不溶性蛋白聚集体相比，超氧化物歧化酶 1（SOD1）的错误折叠与死亡增加有关。结构独立的 SOD1 三聚体导致细胞毒性的机制尚不清楚，但可能是疾病病理的驱动因素。在这里，我们发现了 SOD1 三聚体相互作用组--大脑、脊髓和骨骼肌中潜在的组织选择性蛋白结合伙伴图谱。我们确定了与 SOD1 三聚体相关的结合伙伴和关键通路，发现三聚体可能会影响正常的细胞功能，如中枢神经系统的树突棘形态发生和突触功能以及骨骼肌的细胞代谢。我们发现了 SOD1 三聚体选择性富集基因。我们对 SOD1 三聚体蛋白与 septin-7 的结合进行了详细的计算和生化鉴定。我们的研究突出了不同组织中的关键蛋白和通路，通过 SOD1 三聚体的相互作用揭示了 ALS 遗传和病理生理机制的合理交叉。

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

Structure 生物-生化与分子生物学

CiteScore

8.90

自引率

1.80%

发文量

155

审稿时长

3-8 weeks

期刊介绍： Structure aims to publish papers of exceptional interest in the field of structural biology. The journal strives to be essential reading for structural biologists, as well as biologists and biochemists that are interested in macromolecular structure and function. Structure strongly encourages the submission of manuscripts that present structural and molecular insights into biological function and mechanism. Other reports that address fundamental questions in structural biology, such as structure-based examinations of protein evolution, folding, and/or design, will also be considered. We will consider the application of any method, experimental or computational, at high or low resolution, to conduct structural investigations, as long as the method is appropriate for the biological, functional, and mechanistic question(s) being addressed. Likewise, reports describing single-molecule analysis of biological mechanisms are welcome. In general, the editors encourage submission of experimental structural studies that are enriched by an analysis of structure-activity relationships and will not consider studies that solely report structural information unless the structure or analysis is of exceptional and broad interest. Studies reporting only homology models, de novo models, or molecular dynamics simulations are also discouraged unless the models are informed by or validated by novel experimental data; rationalization of a large body of existing experimental evidence and making testable predictions based on a model or simulation is often not considered sufficient.