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-Structure paper
タイトル | Cryo-EM structure of islet amyloid polypeptide fibrils reveals similarities with amyloid-β fibrils. |
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ジャーナル・号・ページ | Nat Struct Mol Biol, Vol. 27, Issue 7, Page 660-667, Year 2020 |
掲載日 | 2020年6月15日 |
著者 | Christine Röder / Tatsiana Kupreichyk / Lothar Gremer / Luisa U Schäfer / Karunakar R Pothula / Raimond B G Ravelli / Dieter Willbold / Wolfgang Hoyer / Gunnar F Schröder / |
PubMed 要旨 | 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 ...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. |
リンク | Nat Struct Mol Biol / PubMed:32541895 |
手法 | EM (らせん対称) |
解像度 | 4.2 - 8.1 Å |
構造データ | EMDB-10669, PDB-6y1a: EMDB-10670: EMDB-10671: |
化合物 | ChemComp-NH2: |
由来 |
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キーワード | HORMONE / amylin / iapp / amyloid fibril / diabetes |