Astbury Centre for Structural Molecular Biology, School of Molecular & Cellular Biology, University of Leeds, Leeds, UK.
Astbury Centre for Structural Molecular Biology, School of Physics & Astronomy, University of Leeds, Leeds, UK.
Nat Struct Mol Biol. 2020 Nov;27(11):1048-1056. doi: 10.1038/s41594-020-0496-3. Epub 2020 Sep 14.
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.
多肽激素胰淀素聚集成淀粉样沉积物是 2 型糖尿病（T2D）的病理特征。虽然尚未确定 T2D 与淀粉样蛋白之间存在因果关系，但胰淀素中的 S20G 突变与早发性 T2D 有关。在这里，我们报告了野生型人胰淀素及其 S20G 变体的淀粉样纤维的冷冻电镜结构。野生型纤维结构解析至 3.6-Å 分辨率，包含两个原纤维，每个原纤维由 S 形亚基组成。相比之下，S20G 纤维包含两种主要的多态体。它们的结构分别解析至 3.9-Å 和 4.0-Å 分辨率，分别具有一个共同的两原纤维核心，与野生型结构不同。值得注意的是，一种多态体含有另一种具有独特的交叉-β构象的第三个亚基。同一纤维内存在两种不同的骨架构象可能解释了 S20G 增加的聚集倾向，并说明了表面模板纤维组装的潜在结构基础。
