SANTOS, Jaime; CUELLAR, Jorge; PALLARES, Irantzu; BYRD, Emily; LENDS, Alons; MORO, Fernando; ABDUL-SHUKKOOR, Muhammed Bilal; PUJOLS, Jordi; VELASCO-CARNEROS, Lorea; SOBOTT, Frank; OTZEN, Daniel; CALABRESE, Antonio; MUGA, Arturo; PEDERSEN, Jan Skov; LOQUET, Antoine; VALPUESTA, Jose Maria; RADFORD, Sheena; VENTURA, Salvador

doi:10.1021/jacs.4c02262

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Journal of the American Chemical Society. 2024-04-29, vol. 146, n° 18, p. 12702-12711

Résumé en anglais

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.< Réduire

Mots clés en anglais

Genetics

Hydrogen isotopes

Nanofibers

Oligomers

Peptides and proteins

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https://oskar-bordeaux.fr/handle/20.500.12278/204471

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http://dx.doi.org/10.1021/jacs.4c02262

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CBMN : Chimie & de Biologie des Membranes & des Nano-objets - UMR 5248

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A Targetable N-Terminal Motif Orchestrates α-Synuclein Oligomer-to-Fibril Conversion

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