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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Folding of Cu/Zn superoxide dismutase suggests structural hotspots for gain of neurotoxic function in ALS: Parallels to precursors in amyloid disease
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Folding of Cu/Zn superoxide dismutase suggests structural hotspots for gain of neurotoxic function in ALS: Parallels to precursors in amyloid disease

机译：折叠的铜/锌超氧化物歧化酶表明ALS获得神经毒性功能的结构热点：与淀粉样疾病前体平行

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摘要

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease linked to misfolding of the ubiquitous enzyme Cu/Zn superoxide dismutase (SOD). In contrast to other protein-misfolding disorders with similar neuropathogenesis, ALS is not always associated with the in vivo deposition of protein aggregates. Thus, under the assumption that all protein-misfolding disorders share at primary level a similar disease mechanism, ALS constitutes an interesting disease model for identifying the yet-mysterious precursor states from which the cytotoxic pathway emerges. In this study, we have mapped out the conformational repertoire of the apoSOD monomer through analysis of its folding behavior. The results allow us to target the regions of the SOD structure that are most susceptible to unfolding locally under physiological conditions, leading to the exposure of structurally promiscuous interfaces that are normally hidden in the protein's interior. The structure of this putative ALS precursor is strikingly similar to those implicated in amyloid disease.
机译：肌萎缩性侧索硬化症（ALS）是一种神经退行性疾病，与普遍存在的Cu / Zn超氧化物歧化酶（SOD）折叠错误有关。与其他具有类似神经发病机制的蛋白错误折叠疾病相反，ALS并不总是与蛋白聚集体的体内沉积有关。因此，在所有蛋白质错误折叠失调均在初级水平上具有相似的疾病机制的假设下，ALS构成了一种有趣的疾病模型，用于鉴定从中出现细胞毒性途径的尚未神秘的前体状态。在这项研究中，我们通过分析apoSOD单体的折叠行为来绘制其构象库。结果使我们能够确定在生理条件下最容易局部展开的SOD结构区域，从而导致通常隐藏在蛋白质内部的结构混杂界面暴露出来。这种假定的ALS前体的结构与淀粉样蛋白疾病的结构极为相似。

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