Astbury Centre for Structural Molecular Biology, School of Molecular & Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
Astbury Centre for Structural Molecular Biology, School of Molecular & Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
Cell. 2023 Dec 21;186(26):5798-5811.e26. doi: 10.1016/j.cell.2023.11.025.
Cryoelectron microscopy (cryo-EM) has provided unprecedented insights into amyloid fibril structures, including those associated with disease. However, these structures represent the endpoints of long assembly processes, and their relationship to fibrils formed early in assembly is unknown. Consequently, whether different fibril architectures, with potentially different pathological properties, form during assembly remains unknown. Here, we used cryo-EM to determine structures of amyloid fibrils at different times during in vitro fibrillation of a disease-related variant of human islet amyloid polypeptide (IAPP-S20G). Strikingly, the fibrils formed in the lag, growth, and plateau phases have different structures, with new forms appearing and others disappearing as fibrillation proceeds. A time course with wild-type hIAPP also shows fibrils changing with time, suggesting that this is a general property of IAPP amyloid assembly. The observation of transiently populated fibril structures has implications for understanding amyloid assembly mechanisms with potential new insights into amyloid progression in disease.
冷冻电镜（cryo-EM）为淀粉样纤维结构提供了前所未有的见解，包括与疾病相关的结构。然而，这些结构代表了长时间组装过程的终点，而它们与组装早期形成的纤维的关系尚不清楚。因此，在组装过程中是否形成了具有潜在不同病理特性的不同纤维结构尚不清楚。在这里，我们使用 cryo-EM 来确定在体外人胰岛淀粉样多肽（IAPP-S20G）相关变体的纤维形成过程中不同时间的淀粉样纤维的结构。惊人的是，在滞后、生长和平台阶段形成的纤维具有不同的结构，随着纤维的形成，新的形式出现，而其他形式消失。野生型 hIAPP 的时间过程也表明纤维随时间变化，这表明这是 IAPP 淀粉样蛋白组装的一般特性。对瞬态纤维结构的观察对理解淀粉样蛋白组装机制具有潜在的新见解，并可能深入了解疾病中的淀粉样蛋白进展。
