Structural highlights
FunctionIAPP_HUMAN Selectively inhibits insulin-stimulated glucose utilization and glycogen deposition in muscle, while not affecting adipocyte glucose metabolism. Publication Abstract from PubMedAmyloid 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-A 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-beta (Abeta) fibrils, which might account for the epidemiological link between T2D and AD and reports on IAPP-Abeta cross-seeding in vivo. The results structurally link the early-onset T2D IAPP genetic polymorphism (encoding Ser20Gly) with the AD Arctic mutation (Glu22Gly) of Abeta and support the design of inhibitors and imaging probes for IAPP fibrils. Cryo-EM structure of islet amyloid polypeptide fibrils reveals similarities with amyloid-beta fibrils.,Roder C, Kupreichyk T, Gremer L, Schafer LU, Pothula KR, Ravelli RBG, Willbold D, Hoyer W, Schroder GF Nat Struct Mol Biol. 2020 Jul;27(7):660-667. doi: 10.1038/s41594-020-0442-4. Epub, 2020 Jun 15. PMID:32541895[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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