Stabilization and structural analysis of a membrane-associated hIAPP aggregation intermediate.
Stabilization and structural analysis of a membrane-associated hIAPP aggregation intermediate.
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DOI：
10.7554/elife.31226
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发表时间：
2017-11-17
期刊：
影响因子：
7.7
通讯作者：
Ramamoorthy A
中科院分区：
文献类型：
--
作者：
Rodriguez Camargo DC;Korshavn KJ;Jussupow A;Raltchev K;Goricanec D;Fleisch M;Sarkar R;Xue K;Aichler M;Mettenleiter G;Walch AK;Camilloni C;Hagn F;Reif B;Ramamoorthy A
在人类疾病中实施了膜辅助的淀粉样蛋白形成，许多聚集物种加速淀粉样蛋白的形成并诱导细胞死亡，而膜相关的结构可为中间人提供巨大的洞察力。 s解决类型2的结构糖尿病与纳米盘中稳定的糖尿病多肽相关。陷阱淀粉样蛋白中间体证明可以成为剖析蛋白质聚集的复杂错误折叠途径的最强大方法之一。
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.