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