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A population shift between sparsely populated folding intermediates determines amyloidogenicity

Karamanos, TK, Pashley, CL, Kalverda, AP, Thompson, GS, Mayzel, M, Orekhov, VY, Radford, SE (2016) A population shift between sparsely populated folding intermediates determines amyloidogenicity. Journal of the American Chemical Society, 138 . pp. 6271-6280. ISSN 0002-7863. (doi:10.1021/jacs.6b02464) (KAR id:71794)

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http://dx.doi.org/10.1021/jacs.6b02464

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 ?2-microglobulin (?2m) 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.

Item Type: Article
DOI/Identification number: 10.1021/jacs.6b02464
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: Gary Thompson
Date Deposited: 23 Jan 2019 21:46 UTC
Last Modified: 30 May 2019 08:47 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/71794 (The current URI for this page, for reference purposes)
Thompson, GS: https://orcid.org/0000-0001-9399-7636
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