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Structural dissection of the first events following membrane binding of the islet amyloid polypeptide

View ORCID ProfileLucie Khemtemourian, View ORCID ProfileHebah Fatafta, Benoit Davion, Sophie Lecomte, Sabine Castano, View ORCID ProfileBirgit Strodel
doi: https://doi.org/10.1101/2021.12.14.472560
Lucie Khemtemourian
1Université de Bordeaux, CNRS, Bordeaux INP, CBMN, UMR 5248, F-33600 Pessac, France
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  • For correspondence: lucie.khemtemourian@u-bordeaux.fr b.strodel@fz-juelich.de
Hebah Fatafta
2Institute of Biological Information Processing: Structural Biochemistry, Forschungszentrum Jülich, 52428 Jülich, Germany
3JuStruct, Jülich Center for Structural Biology, Forschungszentrum Jülich, 52428 Jülich, Germany
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Benoit Davion
1Université de Bordeaux, CNRS, Bordeaux INP, CBMN, UMR 5248, F-33600 Pessac, France
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Sophie Lecomte
1Université de Bordeaux, CNRS, Bordeaux INP, CBMN, UMR 5248, F-33600 Pessac, France
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Sabine Castano
1Université de Bordeaux, CNRS, Bordeaux INP, CBMN, UMR 5248, F-33600 Pessac, France
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Birgit Strodel
2Institute of Biological Information Processing: Structural Biochemistry, Forschungszentrum Jülich, 52428 Jülich, Germany
3JuStruct, Jülich Center for Structural Biology, Forschungszentrum Jülich, 52428 Jülich, Germany
4Institute of Theoretical and Computational Chemistry, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
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  • ORCID record for Birgit Strodel
  • For correspondence: lucie.khemtemourian@u-bordeaux.fr b.strodel@fz-juelich.de
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ABSTRACT

Amyloid forming proteins are involved in many pathologies and often belong to the class of intrinsically disordered proteins. One of these proteins is the islet amyloid polypeptide (IAPP), which is the main constituent of the amyloid fibrils found in the pancreas of type 2 diabetes patients. The molecular mechanism of IAPP-induced cell death is not yet understood, however it is known that cell membrane plays a dual role, being a catalyst of IAPP aggregation and the target of IAPP toxicity. Using FTIR spectroscopy, transmission electron microscopy, and molecular dynamics simulations we investigate the very first molecular steps following IAPP binding to a lipid membrane. In particular, we assess the combined effects of the charge state of amino-acid residue 18 and the IAPP-membrane interactions on the structures of monomeric and aggregated IAPP. Both our experiments and simulations reveal distinct IAPP-membrane interaction modes for the various IAPP variants. Membrane binding causes IAPP to fold into an amphipathic helix, which in the case of H18K- and H18R-IAPP can easily insert into the membrane. For all IAPP variants but H18E-IAPP, the membrane-bound α-helical structure is an intermediate on the way to IAPP amyloid aggregation, while H18E-IAPP remains in a stable helical conformation. The fibrillar aggregates of wild-type IAPP and H18K-IAPP are dominated by an antiparallel β-sheet conformation, while H18R- and H18A-IAPP exhibit both antiparallel and parallel β-sheets as well as amorphous aggregates. In summary, our results emphasize the importance of residue 18 for the structure and membrane interaction of IAPP. This residue is thus a good target for destabilizing amyloid fibrils of IAPP and inhibit its toxic actions by possible therapeutic molecules.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted December 14, 2021.
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Structural dissection of the first events following membrane binding of the islet amyloid polypeptide
Lucie Khemtemourian, Hebah Fatafta, Benoit Davion, Sophie Lecomte, Sabine Castano, Birgit Strodel
bioRxiv 2021.12.14.472560; doi: https://doi.org/10.1101/2021.12.14.472560
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Structural dissection of the first events following membrane binding of the islet amyloid polypeptide
Lucie Khemtemourian, Hebah Fatafta, Benoit Davion, Sophie Lecomte, Sabine Castano, Birgit Strodel
bioRxiv 2021.12.14.472560; doi: https://doi.org/10.1101/2021.12.14.472560

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