Misfolding of Cu, Zn superoxide dismutase (SOD1) variants may lead to protein aggregation and ultimately amyotrophic lateral sclerosis (ALS). The mechanism and protein conformational changes during this process are complex and remain unclear. To study SOD1 variant aggregation at the molecular level and in solution, we chemically induced aggregation of a mutant variant (G93A SOD1) with trifluoroethanol (TFE) and used both native mass spectrometry (MS) to analyze the intact protein and fast photochemical oxidation of proteins (FPOP) to characterize the structural changes induced by TFE. We found partially unfolded G93A SOD1 monomers prior to oligomerization and identified regions of the N-terminus, C-terminus, and strands β5, β6 accountable for the partial unfolding. We propose that exposure of hydrophobic interfaces of these unstructured regions serves as a precursor to aggregation. Our results provide a possible mechanism and molecular basis for ALS-linked SOD1 misfolding and aggregation.

中文翻译：

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三氟乙醇部分展开导致蛋白质聚集的 G93A SOD1：通过原生质谱和 FPOP 蛋白质足迹进行的研究。

铜、锌超氧化物歧化酶 (SOD1) 变体的错误折叠可能导致蛋白质聚集并最终导致肌萎缩侧索硬化 (ALS)。这一过程中的机制和蛋白质构象变化是复杂的，尚不清楚。为了在分子水平和溶液中研究 SOD1 变异体的聚集，我们用三氟乙醇 (TFE) 化学诱导突变体 (G93A SOD1) 聚集，并使用天然质谱 (MS) 分析完整蛋白质和蛋白质的快速光化学氧化(FPOP) 来表征由 TFE 引起的结构变化。我们在寡聚化之前发现了部分未折叠的 G93A SOD1 单体，并确定了 N 端、C 端和 β5、β6 链​​的区域，这些区域负责部分未折叠。我们建议这些非结构化区域的疏水界面的暴露作为聚集的前兆。我们的结果为 ALS 相关的 SOD1 错误折叠和聚集提供了可能的机制和分子基础。