Abstract

Membrane-assisted amyloid formation is implicated in human diseases, and many of the aggregating species accelerate amyloid formation and induce cell death. While structures of membrane-associated intermediates would provide tremendous insights into the pathology and aid in the design of compounds to potentially treat the diseases, it has not been feasible to overcome the challenges posed by the cell membrane. Here we use NMR experimental constraints to solve the structure of a type-2 diabetes related human islet amyloid polypeptide intermediate stabilized in nanodiscs. ROSETTA and MD simulations resulted in a unique b-strand structure distinct from the conventional amyloid b-hairpin and revealed that the nucleating NFGAIL region remains flexible and accessible within this isolated intermediate, suggesting a mechanism by which membrane-associated aggregation may be propagated. The ability of nanodiscs to trap amyloid intermediates as demonstrated could become one of the most powerful approaches to dissect the complicated misfolding pathways of protein aggregation.

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Author details

  1. Diana C Rodriguez Camargo

    Institute for Advanced Study, Technische Universität München, Garching, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3522-4859
  2. Kyle J Korshavn

    Program in Biophysics, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Alexander Jussupow

    Institute for Advanced Study, Technische Universität München, Garching, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Kolio Raltchev

    Center for Integrated Protein Science Munich, Technische Universität München, Garching, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. David Goricanec

    Center for Integrated Protein Science Munich, Technische Universität München, Garching, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Markus Fleisch

    Helmholtz Zentrum München, Neuherberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Riddhiman Sarkar

    Center for Integrated Protein Science Munich, Technische Universität München, Garching, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Kai Xue

    Helmholtz Zentrum München, Neuherberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Michaela Aichler

    Helmholtz Zentrum München, Neuherberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  10. Gabriele Mettenleiter

    Helmholtz Zentrum München, Neuherberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  11. Axel Karl Walch

    Helmholtz Zentrum München, Neuherberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  12. Carlo Camilloni

    Institute for Advanced Study, Technische Universität München, Garching, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9923-8590
  13. Franz Hagn

    Institute for Advanced Study, Technische Universität München, Garching, Germany
    Competing interests
    The authors declare that no competing interests exist.
  14. Bernd Reif

    Center for Integrated Protein Science Munich, Technische Universität München, Garching, Germany
    Competing interests
    The authors declare that no competing interests exist.
  15. Ayyalusamy Ramamoorthy

    Institute for Advanced Study, Technische Universität München, Garching, Germany
    For correspondence
    ramamoor@umich.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1964-1900

Funding

National Institutes of Health (AG048934)

  • Ayyalusamy Ramamoorthy

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Lewis E Kay, University of Toronto, Canada

Version history

  1. Received: August 13, 2017
  2. Accepted: November 14, 2017
  3. Accepted Manuscript published: November 17, 2017 (version 1)
  4. Version of Record published: November 29, 2017 (version 2)

Copyright

© 2017, Rodriguez Camargo et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Diana C Rodriguez Camargo
  2. Kyle J Korshavn
  3. Alexander Jussupow
  4. Kolio Raltchev
  5. David Goricanec
  6. Markus Fleisch
  7. Riddhiman Sarkar
  8. Kai Xue
  9. Michaela Aichler
  10. Gabriele Mettenleiter
  11. Axel Karl Walch
  12. Carlo Camilloni
  13. Franz Hagn
  14. Bernd Reif
  15. Ayyalusamy Ramamoorthy
(2017)
Stabilization and structural analysis of a membrane-associated hIAPP aggregation intermediate
eLife 6:e31226.
https://doi.org/10.7554/eLife.31226

Share this article

https://doi.org/10.7554/eLife.31226

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