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TitleCryo-EM structure of islet amyloid polypeptide fibrils reveals similarities with amyloid-β fibrils.
Journal, issue, pagesNat Struct Mol Biol, Vol. 27, Issue 7, Page 660-667, Year 2020
Publish dateJun 15, 2020
AuthorsChristine Röder / Tatsiana Kupreichyk / Lothar Gremer / Luisa U Schäfer / Karunakar R Pothula / Raimond B G Ravelli / Dieter Willbold / Wolfgang Hoyer / Gunnar F Schröder /
PubMed AbstractAmyloid 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 ...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.
External linksNat Struct Mol Biol / PubMed:32541895
MethodsEM (helical sym.)
Resolution4.2 - 8.1 Å
Structure data

10669

6y1a

EMDB-10669, PDB-6y1a:
Amyloid fibril structure of islet amyloid polypeptide
Method: EM (helical sym.) / Resolution: 4.2 Å

EMDB-10670:
Amyloid fibril structure of islet amyloid polypeptide - polymorph 2
Method: EM (helical sym.) / Resolution: 4.2 Å

EMDB-10671:
Amyloid fibril structure of islet amyloid polypeptide - polymorph 3
Method: EM (helical sym.) / Resolution: 8.1 Å

Chemicals

ChemComp-NH2:
AMINO GROUP / Amine

Source
  • homo sapiens (human)
KeywordsHORMONE / amylin / iapp / amyloid fibril / diabetes

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