Biasing the native ?-synuclein conformational ensemble towards compact states abolishes aggregation and neurotoxicity.
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ABSTRACT: The aggregation of ?-synuclein (?-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 ?-syn to aggregated neurotoxic forms remains largely unknown. The disordered nature of ?-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 ?-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 ?-syn in different environments. The new covalent link biases the native structural ensemble of ?-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 ?-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.
SUBMITTER: Carija A
PROVIDER: S-EPMC6375061 | biostudies-literature | 2019 Apr
REPOSITORIES: biostudies-literature
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