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Título

A rationally designed six-residue swap generates comparability in the aggregation behavior of α-synuclein and β-synuclein

AutorRoodveldt, Cintia ; Labrador-Garrido, Adahir ; Dobson, Christopher M.; Vendruscolo, Michele
Fecha de publicación22-oct-2012
EditorAmerican Chemical Society
CitaciónBiochemistry 51(44): 8771- 8778 (2012)
ResumenThe aggregation process of α-synuclein, a protein closely associated with Parkinson's disease, is highly sensitive to sequence variations. It is therefore of great importance to understand the factors that define the aggregation propensity of specific mutational variants as well as their toxic behavior in the cellular environment. In this context, we investigated the extent to which the aggregation behavior of α-synuclein can be altered to resemble that of β-synuclein, an aggregation-resistant homologue of α-synuclein not associated with disease, by swapping residues between the two proteins. Because of the vast number of possible swaps, we have applied a rational design procedure to single out a mutational variant, called α2β, in which two short stretches of the sequence in the NAC region have been replaced in α-synuclein from β-synuclein. We find not only that the aggregation rate of α2β is close to that of β-synuclein, being much lower than that of α-synuclein, but also that α2β effectively changes the cellular toxicity of α-synuclein to a value similar to that of β-synuclein upon exposure of SH-SY5Y cells to preformed oligomers. Remarkably, control experiments on the corresponding mutational variant of β-synuclein, called β2α, confirmed that the mutations that we have identified also shift the aggregation behavior of this protein toward that of α-synuclein. These results demonstrate that it is becoming possible to control in quantitative detail the sequence code that defines the aggregation behavior and toxicity of α-synuclein. © 2012 American Chemical Society.
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Versión del editorhttp://dx.doi.org/10.1021/bi300558q
URIhttp://hdl.handle.net/10261/122546
DOI10.1021/bi300558q
Identificadoresissn: 0006-2960
e-issn: 1520-4995
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