Web of Science: 20 cites, Scopus: 21 cites, Google Scholar: cites,
Biasing the native α-synuclein conformational ensemble towards compact states abolishes aggregation and neurotoxicity
Carija, Anita (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Pinheiro, Francisca (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Pujols Pujol, Jordi (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Brás, Inês C. (University Medicine Göttingen)
Lázaro, Diana Fernandes (University Medicine Göttingen)
Santambrogio, Carlo (University of Milano-Bicocca. Dipartimento di Biotecnologie e Bioscienze)
Grandori, Rita (University of Milano-Bicocca. Dipartimento di Biotecnologie e Bioscienze)
Outeiro, Tiago Fleming (Max Planck Institute for Experimental Medicine)
Navarro, Susanna (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Ventura, Salvador (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)

Data: 2019
Resum: The aggregation of α-synuclein (α-syn) into amyloid fibrils is a major pathological hallmark of Parkinson's disease (PD) and other synucleinopathies. The mechanisms underlying the structural transition of soluble and innocuous α-syn to aggregated neurotoxic forms remains largely unknown. The disordered nature of α-syn has hampered the use of structure-based protein engineering approaches to elucidate the molecular determinants of this transition. The recent 3D structure of a pathogenic α-syn fibril provides a template for this kind of studies. The structure supports the NAC domain being a critical element in fibril formation, since it constitutes the core of the fibril, delineating a Greek-key motif. Here, we stapled the ends of this motif with a designed disulfide bond and evaluated its impact on the conformation, aggregation and toxicity of α-syn in different environments. The new covalent link biases the native structural ensemble of α-syn toward compact conformations, reducing the population of fully unfolded species. This conformational bias results in a strongly reduced fibril formation propensity both in the absence and in the presence of lipids and impedes the formation of neurotoxic oligomers. Our study does not support the Greek-key motif being already imprinted in early α-syn assemblies, discarding it as a druggable interface to prevent the initiation of fibrillation. In contrast, it suggests the stabilization of native, compact ensembles as a potential therapeutic strategy to avoid the formation of toxic species and to target the early stages of PD.
Ajuts: Ministerio de Economía y Competitividad BIO2016-783-78310-R
Drets: Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades. Creative Commons
Llengua: Anglès
Document: Article ; recerca ; Versió publicada
Matèria: α-syn, α-synuclein ; PD, Parkinson's disease ; NAC, non-amyloid β-component ; α-synCC, disulfide bridge-containing variant ; CD, circular dichroism ; Th-T, Thioflavin-T ; CR, Congo Red ; TEM, Transmission electron microscopy ; PK, proteinase K ; DOPC, dioleoylphosphatidylcholine ; DMPS, dimyristoylphosphatidylserine ; α-synuclein ; Disulfide bond ; Amyloid ; Protein aggregation ; Parkinson's disease
Publicat a: Redox biology, Vol. 22 (April 2019) , art. 101135, ISSN 2213-2317

DOI: 10.1016/j.redox.2019.101135
PMID: 30769283


15 p, 4.1 MB

El registre apareix a les col·leccions:
Documents de recerca > Documents dels grups de recerca de la UAB > Centres i grups de recerca (producció científica) > Ciències de la salut i biociències > Institut de Biotecnologia i de Biomedicina (IBB)
Articles > Articles de recerca
Articles > Articles publicats

 Registre creat el 2020-07-06, darrera modificació el 2023-04-21



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