Structural Biology & Bio-Informatics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
Chemistry and Chemical Biology, Harvard University, Cambridge, United States.
Elife. 2021 Apr 7;10:e61453. doi: 10.7554/eLife.61453.
Aggregation of Cu-Zn superoxide dismutase (SOD1) is implicated in the motor neuron disease, amyotrophic lateral sclerosis (ALS). Although more than 140 disease mutations of SOD1 are available, their stability or aggregation behaviors in membrane environment are not correlated with disease pathophysiology. Here, we use multiple mutational variants of SOD1 to show that the absence of Zn, and not Cu, significantly impacts membrane attachment of SOD1 through two loop regions facilitating aggregation driven by lipid-induced conformational changes. These loop regions influence both the primary (through Cu intake) and the gain of function (through aggregation) of SOD1 presumably through a shared conformational landscape. Combining experimental and theoretical frameworks using representative ALS disease mutants, we develop a 'co-factor derived membrane association model' wherein mutational stress closer to the Zn (but not to the Cu) pocket is responsible for membrane association-mediated toxic aggregation and survival time scale after ALS diagnosis.
铜锌超氧化物歧化酶（SOD1）的聚集与运动神经元疾病肌萎缩侧索硬化症（ALS）有关。尽管已经有超过 140 种 SOD1 的疾病突变，但它们在膜环境中的稳定性或聚集行为与疾病的病理生理学并不相关。在这里，我们使用 SOD1 的多种突变变体表明，Zn 的缺失，而不是 Cu 的缺失，通过两个环区显著影响 SOD1 与膜的附着，促进由脂质诱导的构象变化引起的聚集。这些环区影响 SOD1 的主要功能（通过 Cu 摄取）和获得功能（通过聚集），可能是通过共享的构象景观。我们使用代表性的 ALS 疾病突变体，结合实验和理论框架，提出了一个“辅因子衍生的膜结合模型”，其中更接近 Zn（而不是 Cu）口袋的突变应激负责膜结合介导的毒性聚集，并在 ALS 诊断后影响存活时间尺度。
