Cited by 180Alzheimer's disease research and treatmentsPancreatic function and diabetesPrion Diseases and Protein Misfolding

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

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Röder, Christine, Kupreichyk, Tatsiana, Gremer, Lothar, Schäfer, Luisa U., Pothula, Karunakar R., Ravelli, Raimond B. G., Willbold, Dieter, Hoyer, Wolfgang +1 more·2020·Nature Structural & Molecular Biology

Published version of a preprint

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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  • Alzheimer's disease/Parkinson's disease and type 2 diabetes mellitus share some pathological commonalities, strongly suggesting the role of antidiabetic drugs in treating neurodegenerative diseases.

    “Previous studies have revealed that AD/PD and type 2 diabetes mellitus share some pathological commonalities, strongly suggesting the role of antidiabetic drugs in treating neurodegenerative diseases,421,422”

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Authors
Röder, C., Kupreichyk, T., Gremer, L., Schäfer, L. U., Pothula, K. R., Ravelli, R. B. G., Willbold, D., Hoyer, W., & Schröder, G. F.
Affiliations
  • Forschungszentrum Jülich (DE)
  • Maastricht University (NL)
Corresponding author
Hoyer, Wolfgang
Venue
Nature Structural & Molecular Biology
Published
2020-06-15
Volume
27
Issue
7
Pages
660-667
ISSN
  • 1545-9985 (ISSN-L)
  • 1545-9993
OpenAlex
W3034727008
Cited by
180
References
84
Citations by year
2026: 18 · 2025: 26 · 2024: 26 · 2023: 22 · 2022: 39 · 2021: 34 · 2020: 15
FWCI
16.54
Type
journal article
Language
en
Open access
Locations
  • Nature Structural & Molecular Biology (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Research Publications (Maastricht University) (publishedVersion, other-oa)
  • Research Publications (Maastricht University) (submittedVersion, other-oa)
Funders
  • Alzheimer Forschung Initiative
  • Universiteit Maastricht
  • Forschungszentrum Jülich
  • Russian Science Foundation (20‐64‐46027)
  • Alzheimer Nederland
  • H2020 European Research Council (726368)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
Keywords
amylin, amyloid-beta, protofilaments, fibril polymorphism, type 2 diabetes, Alzheimer's disease, Arctic mutation, fibril structure, beta cell destruction
MeSH terms
Alzheimer Disease, Diabetes Mellitus, Type 2, Humans, Hydrogen-Ion Concentration, Models, Molecular, Protein Conformation, Amyloid beta-Peptides, Amino Acid Substitution, Cryoelectron Microscopy, Molecular Dynamics Simulation, Islet Amyloid Polypeptide

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