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

Christine Roeder, Tatsiana Kupreichyk, Lothar Gremer, Luisa U. Schaefer, Karunakar R. Pothula, Raimond B. G. Ravelli, Dieter Willbold, Wolfgang Hoyer*, Gunnar F. Schroeder*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Pages (from-to)660-667
Number of pages18
JournalNature Structural and Molecular Biology
Volume27
Issue number7
DOIs
Publication statusPublished - Jul 2020

Keywords

  • ATOMIC-RESOLUTION STRUCTURE
  • ALZHEIMERS-DISEASE
  • S20G MUTATION
  • HUMAN AMYLIN
  • DYNAMICS
  • IAPP
  • MECHANISM
  • SYSTEM
  • GENE
  • CRYSTALLOGRAPHY
  • Human amylin
  • Crystallography
  • Mechanism
  • System
  • S20g mutation
  • Gene
  • Dynamics
  • Atomic-resolution structure
  • Iapp
  • Alzheimers-disease

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