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Amyloid fibril structure of islet amyloid polypeptide by cryo-electron microscopy reveals similarities with amyloid beta

Christine Röder, Tatsiana Kupreichyk, Lothar Gremer, Luisa U. Schäfer, Karunakar R. Pothula, View ORCID ProfileRaimond B. G. Ravelli, Dieter Willbold, Wolfgang Hoyer, View ORCID ProfileGunnar F. Schröder
doi: https://doi.org/10.1101/2020.02.11.944546
Christine Röder
1Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich, 52425 Jülich, Germany
2JuStruct, Centre for Structural Biology, Forschungszentrum Jülich, 52425 Jülich, Germany
3Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
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Tatsiana Kupreichyk
1Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich, 52425 Jülich, Germany
2JuStruct, Centre for Structural Biology, Forschungszentrum Jülich, 52425 Jülich, Germany
3Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
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Lothar Gremer
1Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich, 52425 Jülich, Germany
2JuStruct, Centre for Structural Biology, Forschungszentrum Jülich, 52425 Jülich, Germany
3Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
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Luisa U. Schäfer
1Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich, 52425 Jülich, Germany
2JuStruct, Centre for Structural Biology, Forschungszentrum Jülich, 52425 Jülich, Germany
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Karunakar R. Pothula
1Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich, 52425 Jülich, Germany
2JuStruct, Centre for Structural Biology, Forschungszentrum Jülich, 52425 Jülich, Germany
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Raimond B. G. Ravelli
4The Maastricht Multimodal Molecular Imaging Institute, Maastricht University, 6229 ER, Maastricht, The Netherlands
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  • ORCID record for Raimond B. G. Ravelli
Dieter Willbold
1Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich, 52425 Jülich, Germany
2JuStruct, Centre for Structural Biology, Forschungszentrum Jülich, 52425 Jülich, Germany
3Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
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Wolfgang Hoyer
1Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich, 52425 Jülich, Germany
2JuStruct, Centre for Structural Biology, Forschungszentrum Jülich, 52425 Jülich, Germany
3Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
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  • For correspondence: gu.schroeder@fz-juelich.de wolfgang.hoyer@uni-duesseldorf.de
Gunnar F. Schröder
1Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich, 52425 Jülich, Germany
2JuStruct, Centre for Structural Biology, Forschungszentrum Jülich, 52425 Jülich, Germany
5Physics Department, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
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  • ORCID record for Gunnar F. Schröder
  • For correspondence: gu.schroeder@fz-juelich.de wolfgang.hoyer@uni-duesseldorf.de
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Abstract

A critical role of the hormone islet amyloid polypeptide (IAPP) is vividly discussed for Type 2 Diabetes (T2D), where amyloid deposits in pancreatic islets consisting of fibrillar IAPP have been associated with beta cell loss. Here, we applied cryo-electron microscopy to elucidate the structure of IAPP fibrils prepared at physiological pH and reconstructed densities of three dominant polymorphs. An atomic model of the main polymorph comprising residues 13 – 37 in a density map of 4.2 Å resolution reveals two S-shaped, intertwined protofilaments. The segment 21-NNFGAIL-27, which is essential for IAPP amyloidogenicity, forms the protofilament interface together with tyrosine 37 and the amidated C-terminus. The main IAPP fibril polymorph resembles polymorphs of the Alzheimer disease (AD)-associated amyloid-β peptide (Aβ), which is striking in light of 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 S20G with the early-onset AD Arctic mutation E22G of Aβ, rationalize previous data on IAPP fibrils, help to elucidate mechanisms of amyloid formation and toxicity, and support the design of fibril growth inhibitors as well as imaging probes for early detection of IAPP fibrils.

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Posted February 12, 2020.
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Amyloid fibril structure of islet amyloid polypeptide by cryo-electron microscopy reveals similarities with amyloid beta
Christine Röder, Tatsiana Kupreichyk, Lothar Gremer, Luisa U. Schäfer, Karunakar R. Pothula, Raimond B. G. Ravelli, Dieter Willbold, Wolfgang Hoyer, Gunnar F. Schröder
bioRxiv 2020.02.11.944546; doi: https://doi.org/10.1101/2020.02.11.944546
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Amyloid fibril structure of islet amyloid polypeptide by cryo-electron microscopy reveals similarities with amyloid beta
Christine Röder, Tatsiana Kupreichyk, Lothar Gremer, Luisa U. Schäfer, Karunakar R. Pothula, Raimond B. G. Ravelli, Dieter Willbold, Wolfgang Hoyer, Gunnar F. Schröder
bioRxiv 2020.02.11.944546; doi: https://doi.org/10.1101/2020.02.11.944546

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