Doherty, CPA orcid.org/0000-0001-5685-4716, Ulamec, SM orcid.org/0000-0002-9415-753X, Maya-Martinez, R orcid.org/0000-0002-7371-8051 et al. (6 more authors) (2020) A short motif in the N-terminal region of α-synuclein is critical for both aggregation and function. Nature Structural & Molecular Biology, 27. pp. 249-259. ISSN 1545-9993
Abstract
Aggregation of human α-synuclein (αSyn) is linked to Parkinson’s disease (PD) pathology. The central region of the αSyn sequence contains the non-amyloid β-component (NAC) crucial for aggregation. However, how NAC flanking regions modulate αSyn aggregation remains unclear. Using bioinformatics, mutation and NMR, we identify a 7-residue sequence, named P1 (residues 36–42), that controls αSyn aggregation. Deletion or substitution of this ‘master controller’ prevents aggregation at pH 7.5 in vitro. At lower pH, P1 synergises with a sequence containing the preNAC region (P2, residues 45–57) to prevent aggregation. Deleting P1 (ΔP1) or both P1 and P2 (ΔΔ) also prevents age-dependent αSyn aggregation and toxicity in C. elegans models and prevents αSyn-mediated vesicle fusion by altering the conformational properties of the protein when lipid bound. The results highlight the importance of a master-controller sequence motif that controls both αSyn aggregation and function—a region that could be targeted to prevent aggregation in disease.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2020 Springer Nature Limited |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Structural Molecular Biology 2 (Leeds) |
Funding Information: | Funder Grant number EU - European Union 322408 Wellcome Trust 204963/Z/16/Z NC3Rs NC/P001203/1 |
Depositing User: | Symplectic Publications |
Date Deposited: | 24 Jan 2020 13:56 |
Last Modified: | 19 Dec 2024 14:58 |
Status: | Published |
Publisher: | Nature Research |
Identification Number: | 10.1038/s41594-020-0384-x |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:155980 |