Aggregation of Cu-Zn superoxide dismutase (SOD1) is implicated in the motor neuron disease, 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.

中文翻译：

---

金属辅因子锌和相互作用的膜在体外ALS模型中调节SOD1构象-聚集态。

铜锌超氧化物歧化酶（SOD1）的聚集与运动神经元疾病，ALS。尽管有140种以上的SOD1疾病突变可用，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无关。在这里，我们使用SOD1的多个突变变体来显示，Zn而不是Cu的缺失通过两个环区域显着影响SOD1的膜附着，促进了脂质诱导的构象变化驱动的聚集。这些环区域大概通过共同的构象态势影响SOD1的主要（通过摄入铜）和功能获得（通过聚集）。结合使用具有代表性的ALS疾病突变体的实验和理论框架，