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Página principal > Artículos > Artículos publicados > A Targetable N-Terminal Motif Orchestrates α-Synuclein Oligomer-to-Fibril Conversion |
Fecha: | 2024 |
Resumen: | 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. |
Ayudas: | Agencia Estatal de Investigación BIO2017-91475-EXP Agencia Estatal de Investigación PID2022-137963OB-I00 Agencia Estatal de Investigación PID2019-105017RB-I00 Agencia Estatal de Investigación PID2019-111068GB-I00 Ministerio de Ciencia e Innovación FPU17/01157 Agencia Estatal de Investigación PID2019-105872 GB-I00 Agencia Estatal de Investigación PID2022-137175NB-I00 |
Nota: | Altres ajuts: acords transformatius de la UAB |
Derechos: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. |
Lengua: | Anglès |
Documento: | Article ; recerca ; Versió publicada |
Publicado en: | Journal of the American Chemical Society, Vol. 146, Issue 18 (May 2024) , p. 12702−12711, ISSN 1520-5126 |
10 p, 10.4 MB |