Familial Parkinson’s disease associated mutations alter the site-specific microenvironment and dynamics of {alpha}-Synuclein [Molecular Biophysics]

January 29th, 2015 by Sahay, S., Ghosh, D., Dwivedi, S., Anoop, A., Mohite, G. M., Kombrabail, M., Krishnamoorthy, G., Maji, S. K.

Human α-Synuclein (α-Syn) is a natively unstructured protein, whose aggregation into amyloid fibrils is associated with Parkinson's disease (PD) pathogenesis. The mutations of α-Syn, E46K, A53T and A30P have been linked to familial form of PD. The in vitro aggregation studies suggest that increased propensity to form non-fibrillar oligomers is the shared property of these familial PD associated mutants. However the structural basis of the altered aggregation propensities of these PD associated mutants is not yet clear. To understand this, we studied the site-specific structural dynamics of wild type (wt) α-Syn and its three PD mutants (A53T, E46K and A30P). Tryptophan (Trp) was substituted at the N-terminus, central hydrophobic region and C-terminus of all α-Syns. Using various biophysical techniques including time-resolved fluorescence studies, we show that irrespective of similar secondary structure and early oligomerization propensities, familial PD associated mutations alter the site-specific microenvironment, solvent exposure and conformational flexibility of the protein. Our results further show that the common structural feature of the three PD associated mutants is more compact and rigid sites at their N- and C-terminus compared to wt α-Syn, which may facilitate the formation of partially folded intermediate that eventually leads to their increased oligomerization propensities.
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