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-angstrom 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-beta (A beta) fibrils, which might account for the epidemiological link between T2D and AD and reports on IAPP-A beta cross-seeding in vivo. The results structurally link the early-onset T2D IAPP genetic polymorphism (encoding Ser20Gly) with the AD Arctic mutation (Glu22Gly) of A beta and support the design of inhibitors and imaging probes for IAPP fibrils.

Cryo-EM analyses of amyloid fibrils formed by synthetic human IAPP show an S-fold for the main polymorph, with the backbone superimposable with those of amyloid-beta fibrils in antiparallel arrangement.

Original languageEnglish
Pages (from-to)660-+
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

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