Santos, J., Cuellar, J., Pallares, I. et al. (15 more authors) (2024) A Targetable N-Terminal Motif Orchestrates α-Synuclein Oligomer-to-Fibril Conversion. Journal of the American Chemical Society. ISSN 0002-7863
Abstract
Oligomeric species populated during α-synuclein aggregation are considered key drivers of neurodegeneration in Parkinson’s disease. However, the development of oligomer-targeting therapeutics is constrained by our limited knowledge of their structure and the molecular determinants driving their conversion to fibrils. Phenol-soluble modulin α3 (PSMα3) is a nanomolar peptide binder of α-synuclein oligomers that inhibits aggregation by blocking oligomer-to-fibril conversion. Here, we investigate the binding of PSMα3 to α-synuclein oligomers to discover the mechanistic basis of this protective activity. We find that PSMα3 selectively targets an α-synuclein N-terminal motif (residues 36–61) that populates a distinct conformation in the mono- and oligomeric states. This α-synuclein region plays a pivotal role in oligomer-to-fibril conversion as its absence renders the central NAC domain insufficient to prompt this structural transition. The hereditary mutation G51D, associated with early onset Parkinson’s disease, causes a conformational fluctuation in this region, leading to delayed oligomer-to-fibril conversion and an accumulation of oligomers that are resistant to remodeling by molecular chaperones. Overall, our findings unveil a new targetable region in α-synuclein oligomers, advance our comprehension of oligomer-to-amyloid fibril conversion, and reveal a new facet of α-synuclein pathogenic mutations.
Metadata
Item Type: | Article | ||||
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2024 The Authors. Published by American Chemical Society. This publication is licensed under CC-BY 4.0. |
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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 (Leeds) | ||||
Funding Information: |
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Depositing User: | Symplectic Publications | ||||
Date Deposited: | 18 Apr 2024 08:43 | ||||
Last Modified: | 03 May 2024 12:29 | ||||
Status: | Published online | ||||
Publisher: | American Chemical Society | ||||
Identification Number: | https://doi.org/10.1021/jacs.4c02262 |