The overall objective of this proposal is to determine the effect of specific disease associated post-translational modifications, more specifically phosphorylation and nitration, on modulating the structural and biochemical properties of a-synuclein. In detail, we plan to assess the effect of these modifications on i) the structure of monomeric and membrane bound a-synuclein; ii) the oliogmerization and fibrillogenesis of a-syn; iii) subcellular localization and targeting of a-syn to specific cellular compartments. Towards this goal, we plan to use a combination of chemical biology and semisynthetic strategies to 1) synthesize a-syn variants that are modified at specific sites 2) make use of caged amino acids and fluorescent tags to allow temporal and spatial induction and control of post-translational modification in living cells.
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