Single residue modulators of amyloid formation in the N-terminal P1-region of α-synuclein

Abstract

Alpha-synuclein (αSyn) is a protein involved in neurodegenerative disorders including Parkinson’s disease. Amyloid formation of αSyn can be modulated by the ‘P1 region’ (residues 36-42). Here, mutational studies of P1 reveal that Y39A and S42A extend the lag-phase of αSyn amyloid formation in vitro and rescue amyloid-associated cytotoxicity in C. elegans. Additionally, L38I αSyn forms amyloid fibrils more rapidly than WT, L38A has no effect, but L38M does not form amyloid fibrils in vitro and protects from proteotoxicity. Swapping the sequence of the two residues that differ in the P1 region of the paralogue γSyn to those of αSyn did not enhance fibril formation for γSyn. Peptide binding experiments using NMR showed that P1 synergises with residues in the NAC and C-terminal regions to initiate aggregation. The remarkable specificity of the interactions that control αSyn amyloid formation, identifies this region as a potential target for therapeutics, despite their weak and transient nature.

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Item Type:	Article
Authors/Creators:	Ulamec, SM Maya-Martinez, R Byrd, EJ https://orcid.org/0000-0002-9876-1400 Dewison, KM Xu, Y Willis, LF https://orcid.org/0000-0001-6616-3716 Sobott, F https://orcid.org/0000-0001-9029-1865 Heath, GR https://orcid.org/0000-0001-6431-2191 Van Oosten-Hawle, P Buchman, VL Radford, SE https://orcid.org/0000-0002-3079-8039 Brockwell, DJ https://orcid.org/0000-0002-0802-5937
Copyright, Publisher and Additional Information:	© The Author(s) 2022. 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/.
Keywords:	Intrinsically disordered proteins; Parkinson's disease; Protein aggregation; Structural biology
Dates:	Published: 25 August 2022 Published (online): 25 August 2022 Accepted: 10 August 2022
Institution:	The University of Leeds
Academic Units:	The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Physics and Astronomy (Leeds) > Molecular & Nanoscale Physics The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Structural Molecular Biology (Leeds)
Depositing User:	Symplectic Publications
Date Deposited:	19 Aug 2022 11:36
Last Modified:	25 Jun 2023 23:04
Status:	Published
Publisher:	Nature Research
Identification Number:	10.1038/s41467-022-32687-1
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:190179

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Single residue modulators of amyloid formation in the N-terminal P1-region of α-synuclein

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