Cryo-EM structure of islet amyloid polypeptide fibrils reveals similarities with amyloid-β fibrils
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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”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [421]
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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
- ORCID
- 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
- bronze
- doi.org
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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