Journal Article

FZJ-2020-02940

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Cryo-EM structure of islet amyloid polypeptide fibrils reveals similarities with amyloid-β fibrils

Röder, C.FZJ* ; Kupreichyk, T.FZJ* ; Gremer, L.FZJ* ; Schäfer, L. U.FZJ* ; Pothula, K. R.FZJ* ; Ravelli, R. B. G. ; Willbold, D.FZJ* ; Hoyer, W.FZJ* ; Schröder, G. F. (Corresponding author)FZJ*

2020
Nature Publishing Group London [u.a.]

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Please use a persistent id in citations: http://hdl.handle.net/2128/26817  doi:10.1038/s41594-020-0442-4

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.

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Contributing Institute(s):

1. Strukturbiochemie (IBI-7)

Research Program(s):

1. 551 - Functional Macromolecules and Complexes (POF3-551) (POF3-551)

Appears in the scientific report 2020

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