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

Autor: Röder C; Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich, Jülich, Germany.; Jülich Centre for Structural Biology (JuStruct), Forschungszentrum Jülich, Jülich, Germany.; Institut für Physikalische Biologie, Heinrich Heine University Düsseldorf, Düsseldorf, Germany., Kupreichyk T; Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich, Jülich, Germany.; Jülich Centre for Structural Biology (JuStruct), Forschungszentrum Jülich, Jülich, Germany.; Institut für Physikalische Biologie, Heinrich Heine University Düsseldorf, Düsseldorf, Germany., Gremer L; Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich, Jülich, Germany.; Jülich Centre for Structural Biology (JuStruct), Forschungszentrum Jülich, Jülich, Germany.; Institut für Physikalische Biologie, Heinrich Heine University Düsseldorf, Düsseldorf, Germany., Schäfer LU; Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich, Jülich, Germany.; Jülich Centre for Structural Biology (JuStruct), Forschungszentrum Jülich, Jülich, Germany., Pothula KR; Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich, Jülich, Germany.; Jülich Centre for Structural Biology (JuStruct), Forschungszentrum Jülich, Jülich, Germany., Ravelli RBG; The Multimodal Molecular Imaging Institute, Maastricht University, Maastricht, the Netherlands., Willbold D; Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich, Jülich, Germany.; Jülich Centre for Structural Biology (JuStruct), Forschungszentrum Jülich, Jülich, Germany.; Institut für Physikalische Biologie, Heinrich Heine University Düsseldorf, Düsseldorf, Germany., Hoyer W; Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich, Jülich, Germany. wolfgang.hoyer@uni-duesseldorf.de.; Jülich Centre for Structural Biology (JuStruct), Forschungszentrum Jülich, Jülich, Germany. wolfgang.hoyer@uni-duesseldorf.de.; Institut für Physikalische Biologie, Heinrich Heine University Düsseldorf, Düsseldorf, Germany. wolfgang.hoyer@uni-duesseldorf.de., Schröder GF; Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich, Jülich, Germany. gu.schroeder@fz-juelich.de.; Jülich Centre for Structural Biology (JuStruct), Forschungszentrum Jülich, Jülich, Germany. gu.schroeder@fz-juelich.de.; Physics Department, Heinrich Heine University Düsseldorf, Düsseldorf, Germany. gu.schroeder@fz-juelich.de.
Jazyk: angličtina
Zdroj: Nature structural & molecular biology [Nat Struct Mol Biol] 2020 Jul; Vol. 27 (7), pp. 660-667. Date of Electronic Publication: 2020 Jun 15.
DOI: 10.1038/s41594-020-0442-4
Abstrakt: 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.
Databáze: MEDLINE
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