Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich, Jülich, Germany.
Jülich Centre for Structural Biology (JuStruct), Forschungszentrum Jülich, Jülich, Germany.
Nat Struct Mol Biol. 2020 Jul;27(7):660-667. doi: 10.1038/s41594-020-0442-4. Epub 2020 Jun 15.
Amyloid deposits consisting of fibrillar islet amyloid polypeptide (IAPP) in pancreatic islets are associated with beta-cell loss and have been implicated in type 2 diabetes (T2D). Here, we applied cryo-EM to reconstruct densities of three dominant IAPP fibril polymorphs, formed in vitro from synthetic human IAPP. An atomic model of the main polymorph, built from a density map of 4.2-Å resolution, reveals two S-shaped, intertwined protofilaments. The segment 21-NNFGAIL-27, essential for IAPP amyloidogenicity, forms the protofilament interface together with Tyr37 and the amidated C terminus. The S-fold resembles polymorphs of Alzheimer's disease (AD)-associated amyloid-β (Aβ) fibrils, which might account for the epidemiological link between T2D and AD and reports on IAPP-Aβ cross-seeding in vivo. The results structurally link the early-onset T2D IAPP genetic polymorphism (encoding Ser20Gly) with the AD Arctic mutation (Glu22Gly) of Aβ and support the design of inhibitors and imaging probes for IAPP fibrils.
胰岛内由纤维状胰岛淀粉样多肽（IAPP）组成的淀粉样沉积物与β细胞丢失有关，并与 2 型糖尿病（T2D）有关。在这里，我们应用冷冻电镜重建了三种主要的 IAPP 纤维多晶型物的密度，这些多晶型物是从合成的人 IAPP 体外形成的。从分辨率为 4.2-Å 的密度图构建的主要多晶型物的原子模型揭示了两个 S 形相互交织的原纤维。对于 IAPP 淀粉样变性至关重要的片段 21-NNFGAIL-27 与 Tyr37 和酰胺化 C 末端一起形成原纤维界面。S 折叠类似于阿尔茨海默病（AD）相关淀粉样-β（Aβ）纤维的多晶型物，这可能解释了 T2D 和 AD 之间的流行病学联系以及关于体内 IAPP-Aβ 交叉播种的报道。这些结果在结构上把早发性 T2D IAPP 遗传多态性（编码 Ser20Gly）与 Aβ 的 AD 北极突变（Glu22Gly）联系起来，并支持 IAPP 纤维抑制剂和成像探针的设计。
