Impact of Phosphorylation on alpha-Synuclein Structural Determinants

Abstract

AbstractSerine 129 and, to a lesser extent, serine 87 can appear phosphorylated in the intrinsically disordered protein humanα-synuclein (AS), a key player in Parkinson’s disease, where it accumulates in proteinaceous aggregates. Intriguingly, both phosphorylations are located in a highly negative potential region of the protein. Here we used molecular simulation to provide insight in the selective phosphorylation by polo-like kinase 2 (PLK2), in both monomeric and fibrillar forms of AS. We suggest that phosphorylation does not impact on the structural determinants of the physiological AS conformational ensemble, as the phosphate group is mostly solvated. Our findings are consistent with experimental data on the non-acetylated, non-physiological form of the protein. The phosphate groups of pAS may be solvated also in the aggregated form.