Doherty, CPA, Ulamec, SM, Maya-Martinez, R 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
Authors/Creators: |
|
||||||||
---|---|---|---|---|---|---|---|---|---|
Copyright, Publisher and Additional Information: | © 2020 Springer Nature Limited | ||||||||
Dates: |
|
||||||||
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: |
|
||||||||
Depositing User: | Symplectic Publications | ||||||||
Date Deposited: | 24 Jan 2020 13:56 | ||||||||
Last Modified: | 20 Oct 2020 10:22 | ||||||||
Status: | Published | ||||||||
Publisher: | Nature Research | ||||||||
Identification Number: | https://doi.org/10.1038/s41594-020-0384-x | ||||||||
Related URLs: |