Membrane-assisted amyloid formation is implicated in human diseases, and many of the aggregating species accelerate amyloid formation and induce cell death. While structures of membrane-associated intermediates would provide tremendous insights into the pathology and aid in the design of compounds to potentially treat the diseases, it has not been feasible to overcome the challenges posed by the cell membrane. Here, we use NMR experimental constraints to solve the structure of a type-2 diabetes related human islet amyloid polypeptide intermediate stabilized in nanodiscs. ROSETTA and MD simulations resulted in a unique β-strand structure distinct from the conventional amyloid β-hairpin and revealed that the nucleating NFGAIL region remains flexible and accessible within this isolated intermediate, suggesting a mechanism by which membrane-associated aggregation may be propagated. The ability of nanodiscs to trap amyloid intermediates as demonstrated could become one of the most powerful approaches to dissect the complicated misfolding pathways of protein aggregation.

中文翻译：

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膜相关 hIAPP 聚集中间体的稳定性和结构分析

膜辅助淀粉样蛋白形成与人类疾病有关，许多聚集的物种加速淀粉样蛋白形成并诱导细胞死亡。虽然膜相关中间体的结构将提供对病理学的深刻见解并有助于设计潜在治疗疾病的化合物，但克服细胞膜带来的挑战并不可行。在这里，我们使用 NMR 实验约束来解决稳定在纳米圆盘中的 2 型糖尿病相关人胰岛淀粉样多肽中间体的结构。ROSETTA 和 MD 模拟产生了一种独特的 β 链结构，不同于传统的淀粉样蛋白 β-发夹，并表明成核 NFGAIL 区域在这个孤立的中间体中保持灵活和可接近，暗示了一种可以传播膜相关聚集的机制。所证明的纳米圆盘捕获淀粉样蛋白中间体的能力可能成为剖析复杂的蛋白质聚集错误折叠途径的最有效方法之一。