Aggregation of the peptide hormone amylin into amyloid deposits is a pathological hallmark of type-2 diabetes (T2D). While no causal link between T2D and amyloid has been established, the S20G mutation in amylin is associated with early-onset T2D. Here we report cryo-EM structures of amyloid fibrils of wild-type human amylin and its S20G variant. The wild-type fibril structure, solved to 3.6-Å resolution, contains two protofilaments, each built from S-shaped subunits. S20G fibrils, by contrast, contain two major polymorphs. Their structures, solved at 3.9-Å and 4.0-Å resolution, respectively, share a common two-protofilament core that is distinct from the wild-type structure. Remarkably, one polymorph contains a third subunit with another, distinct, cross-β conformation. The presence of two different backbone conformations within the same fibril may explain the increased aggregation propensity of S20G, and illustrates a potential structural basis for surface-templated fibril assembly.

肽激素胰淀素聚集成淀粉样蛋白沉积物是 2 型糖尿病 (T2D) 的病理标志。虽然尚未确定 T2D 与淀粉样蛋白之间的因果关系，但胰淀素中的 S20G 突变与早发性 T2D 相关。在这里，我们报告了野生型人胰岛淀粉样蛋白及其 S20G 变体的淀粉样蛋白原纤维的冷冻电镜结构。解析为 3.6-Å 分辨率的野生型原纤维结构包含两条原丝，每条原丝均由 S 形亚基构成。相比之下，S20G 原纤维包含两种主要的多晶型物。它们的结构分别以 3.9-Å 和 4.0-Å 分辨率解析，共享一个共同的双原丝核心，该核心不同于野生型结构。值得注意的是，一种多晶型物包含具有另一种不同的交叉β构象的第三个亚基。