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

Ulamec, Sabine M., Maya-Martinez, Roberto, Byrd, Emily J., Dewison, Katherine M., Xu, Yong, Willis, Leon F., Sobott, Frank, Heath, George R., van Oosten Hawle, Patricija, Buchman, Vladimir L. ORCID: https://orcid.org/0000-0002-7631-8352, Radford, Sheena E. and Brockwell, David J. 2022. Single residue modulators of amyloid formation in the N-terminal P1-region of α-synuclein. Nature Communications 13 (1) , 4986. 10.1038/s41467-022-32687-1

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Abstract

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.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Biosciences
Additional Information: License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher: Nature Research
ISSN: 2041-1723
Date of First Compliant Deposit: 26 August 2022
Date of Acceptance: 10 August 2022
Last Modified: 10 Nov 2022 11:52
URI: https://orca.cardiff.ac.uk/id/eprint/152158

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