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

dc.rights.licenseopenen_US
dc.contributor.authorSANTOS, Jaime
dc.contributor.authorCUELLAR, Jorge
dc.contributor.authorPALLARES, Irantzu
dc.contributor.authorBYRD, Emily
hal.structure.identifierChimie et Biologie des Membranes et des Nanoobjets [CBMN]
dc.contributor.authorLENDS, Alons
dc.contributor.authorMORO, Fernando
dc.contributor.authorABDUL-SHUKKOOR, Muhammed Bilal
dc.contributor.authorPUJOLS, Jordi
dc.contributor.authorVELASCO-CARNEROS, Lorea
dc.contributor.authorSOBOTT, Frank
dc.contributor.authorOTZEN, Daniel
dc.contributor.authorCALABRESE, Antonio
dc.contributor.authorMUGA, Arturo
dc.contributor.authorPEDERSEN, Jan Skov
hal.structure.identifierChimie et Biologie des Membranes et des Nanoobjets [CBMN]
dc.contributor.authorLOQUET, Antoine
dc.contributor.authorVALPUESTA, Jose Maria
dc.contributor.authorRADFORD, Sheena
dc.contributor.authorVENTURA, Salvador
dc.date.accessioned2025-01-22T10:30:08Z
dc.date.available2025-01-22T10:30:08Z
dc.date.issued2024-04-29
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/204471
dc.description.abstractEnOligomeric 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.
dc.language.isoENen_US
dc.rightsAttribution-NonCommercial-NoDerivs 3.0 United States*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/us/*
dc.subject.enGenetics
dc.subject.enHydrogen isotopes
dc.subject.enNanofibers
dc.subject.enOligomers
dc.subject.enPeptides and proteins
dc.title.enA Targetable N-Terminal Motif Orchestrates α-Synuclein Oligomer-to-Fibril Conversion
dc.typeArticle de revueen_US
dc.identifier.doi10.1021/jacs.4c02262en_US
dc.subject.halChimie/Matériauxen_US
dc.identifier.pubmed38683963en_US
bordeaux.journalJournal of the American Chemical Societyen_US
bordeaux.page12702-12711en_US
bordeaux.volume146en_US
bordeaux.hal.laboratoriesCBMN : Chimie & de Biologie des Membranes & des Nano-objets - UMR 5248en_US
bordeaux.issue18en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.institutionBordeaux INPen_US
bordeaux.institutionCNRSen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
hal.popularnonen_US
hal.audienceInternationaleen_US
hal.exportfalse
dc.rights.ccCC BY-NC-NDen_US
bordeaux.COinSctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Journal%20of%20the%20American%20Chemical%20Society&rft.date=2024-04-29&rft.volume=146&rft.issue=18&rft.spage=12702-12711&rft.epage=12702-12711&rft.au=SANTOS,%20Jaime&CUELLAR,%20Jorge&PALLARES,%20Irantzu&BYRD,%20Emily&LENDS,%20Alons&rft.genre=article


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