Structural effects of the highly protective V127 polymorphism on human prion protein

Abstract

Prion diseases, a group of incurable, lethal neurodegenerative disorders of mammals including humans, are caused by prions, assemblies of misfolded host prion protein (PrP). A single point mutation (G127V) in human PrP prevents prion disease, however the structural basis for its protective effect remains unknown. Here we show that the mutation alters and constrains the PrP backbone conformation preceding the PrP β-sheet, stabilising PrP dimer interactions by increasing intermolecular hydrogen bonding. It also markedly changes the solution dynamics of the β2-α2 loop, a region of PrP structure implicated in prion transmission and cross-species susceptibility. Both of these structural changes may affect access to protein conformers susceptible to prion formation and explain its profound effect on prion disease.

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Item Type:	Article
Authors/Creators:	Hosszu, L.L.P. Conners, R. Sangar, D. Batchelor, M. Sawyer, E.B. Fisher, S. Cliff, M.J. Hounslow, A.M. McAuley, K. Brady, R.L. Jackson, G.S. Bieschke, J. Waltho, J.P. https://orcid.org/0000-0002-7402-5492 Collinge, J.
Copyright, Publisher and Additional Information:	© 2020 The Author(s). 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/.
Dates:	Accepted: 3 July 2020 Published (online): 29 July 2020 Published: December 2020
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield) > Department of Molecular Biology and Biotechnology (Sheffield)
Funding Information:	Funder Grant number Medical Research Council N/A
Depositing User:	Symplectic Sheffield
Date Deposited:	06 Aug 2020 07:15
Last Modified:	06 Aug 2020 07:15
Status:	Published
Publisher:	Springer Nature
Refereed:	Yes
Identification Number:	10.1038/s42003-020-01126-6
Related URLs:	PubMed URL
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:164068

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Structural effects of the highly protective V127 polymorphism on human prion protein

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