Yee, AW, Aldeghi, M, Blakeley, MP, Ostermann, A, Mas, PJ, Moulin, M, de Sanctis, D, Bowler, MW, Mueller-Dieckmann, C, Mitchell, EP, Haertlein, M, de Groot, BL, Boeri Erba, E and Forsyth, VT (2019) A molecular mechanism for transthyretin amyloidogenesis. Nature Communications, 10 (1).

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Abstract

Human transthyretin (TTR) is implicated in several fatal forms of amyloidosis. Many mutations of TTR have been identified; most of these are pathogenic, but some offer protective effects. The molecular basis underlying the vastly different fibrillation behaviours of these TTR mutants is poorly understood. Here, on the basis of neutron crystallography, native mass spectrometry and modelling studies, we propose a mechanism whereby TTR can form amyloid fibrils via a parallel equilibrium of partially unfolded species that proceeds in favour of the amyloidogenic forms of TTR. It is suggested that unfolding events within the TTR monomer originate at the C-D loop of the protein, and that destabilising mutations in this region enhance the rate of TTR fibrillation. Furthermore, it is proposed that the binding of small molecule drugs to TTR stabilises non-amyloidogenic states of TTR in a manner similar to that occurring for the protective mutants of the protein.

Item Type: Article
Additional Information: Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Uncontrolled Keywords: biochemistry; mass spectrometry; molecular dynamics; neurodegenerative diseases; x-ray crystallography
Subjects: Q Science > QD Chemistry
Divisions: Faculty of Natural Sciences > School of Chemical and Physical Sciences
Related URLs:
Depositing User: Symplectic
Date Deposited: 13 Mar 2019 15:59
Last Modified: 18 Mar 2019 10:04
URI: http://eprints.keele.ac.uk/id/eprint/6051

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