Karamanos, TK, Pashley, CL, Kalverda, AP et al. (4 more authors) (2016) A population shift between sparsely populated folding intermediates determines amyloidogenicity. Journal of the American Chemical Society, 138 (19). pp. 6271-6280. ISSN 0002-7863
Abstract
The balance between protein folding and misfolding is a crucial determinant of amyloid assembly. Transient intermediates that are sparsely populated during protein folding have been identified as key players in amyloid aggregation. However, due to their ephemeral nature, structural characterization of these species remains challenging. Here, using the power of non-uniformly sampled NMR methods we investigate the folding pathway of amyloidogenic and non-amyloidogenic variants of β2-microglobulin (β2m) in atomic detail. Despite folding via common intermediate states, we show that the decreased population of the ITrans state and population of a less stable, more dynamic species ablates amyloid formation by increasing the energy barrier for amyloid assembly. The results show that subtle changes in conformational dynamics can have a dramatic effect in determining whether a protein is amyloidogenic, without perturbation of the mechanism of protein folding.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2016 American Chemical Society. This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited. |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Molecular Virology (Leeds) The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > NMR (Leeds) The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Structural Molecular Biology (Leeds) |
Funding Information: | Funder Grant number Wellcome Trust 094232/Z/10/Z |
Depositing User: | Symplectic Publications |
Date Deposited: | 10 May 2016 10:28 |
Last Modified: | 05 Oct 2017 16:17 |
Published Version: | http://dx.doi.org/10.1021/jacs.6b02464 |
Status: | Published |
Publisher: | American Chemical Society |
Identification Number: | 10.1021/jacs.6b02464 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:99405 |