Stabilization and structural analysis of a membrane-associated hIAPP aggregation intermediate
- Technische Universität München, Germany
- University of Michigan, United States
- Helmholtz Zentrum München, Germany
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.
Article and author information
Author details
Diana C Rodriguez Camargo
Ayyalusamy Ramamoorthy
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
- Lewis E Kay, University of Toronto, Canada
Version history
- Received: August 13, 2017
- Accepted: November 14, 2017
- Accepted Manuscript published: November 17, 2017 (version 1)
- 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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Stabilization and structural analysis of a membrane-associated hIAPP
aggregation intermediate
eLife 6:e31226.
https://doi.org/10.7554/eLife.31226
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