| Literature DB >> 32541895 |
Christine Röder1,2,3, Tatsiana Kupreichyk1,2,3, Lothar Gremer1,2,3, Luisa U Schäfer1,2, Karunakar R Pothula1,2, Raimond B G Ravelli4, Dieter Willbold1,2,3, Wolfgang Hoyer5,6,7, Gunnar F Schröder8,9,10.
Abstract
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.Entities:
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Year: 2020 PMID： 32541895 DOI： 10.1038/s41594-020-0442-4
Source DB: PubMed Journal: Nat Struct Mol Biol ISSN： 1545-9985 Impact factor: 15.369