Cryo-EM structure of islet amyloid polypeptide fibrils reveals similarities with amyloid-β fibrils

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 synthe...

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Bibliographic Details
Published in:Nature Structural & Molecular Biology
Main Authors: Roeder, Christine, Kupreichyk, Tatsiana, Gremer, Lothar, Schaefer, Luisa U., Pothula, Karunakar R., Ravelli, Raimond B. G., Willbold, Dieter, Hoyer, Wolfgang, Schroeder, Gunnar F.
Format: Article in Journal/Newspaper
Language:English
Published: 2020
Subjects:
ATOMIC-RESOLUTION STRUCTURE
ALZHEIMERS-DISEASE
S20G MUTATION
HUMAN AMYLIN
DYNAMICS
IAPP
MECHANISM
SYSTEM
GENE
CRYSTALLOGRAPHY
Arctic
Online Access:https://cris.maastrichtuniversity.nl/en/publications/3ff42efb-4efb-4806-977d-a2574aa9dced
https://doi.org/10.1038/s41594-020-0442-4
https://cris.maastrichtuniversity.nl/ws/files/87990313/Ravelli_2020_CryoEM_structure_of_islet_amyloid.pdf
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Summary: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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