Pt(iv) complex selectively oxidizes alpha-synuclein methionine as disclosed by NMR

Abstract

Alpha-synuclein (αS) is an intrinsically disordered neuronal protein, and the oxidative modification of αS promotes its oligomerization and accumulation in Parkinson's disease. By combining high-resolution NMR spectroscopy and mass spectrometry, we investigated the interaction of a platinum(IV) complex with αS at the residual specific resolution. The data indicate that the Pt(IV) complex was able to oxidize the methionine sidechains in a distinct manner under physiological conditions. The C-terminal M116 and M127 were first oxidized in a mutually exclusive manner followed by the oxidation of M5 with a large excess of Pt(IV), whereas M1 could not be oxidized. The oxidized methionines were unable to bind to Pt(II) and the Pt(II)-coordinated methionine could not be oxidized by H₂O₂. These results show the distinct oxidation preferences of αS methionines exhibited by the Pt(IV) complex at the residual specific resolution and imply the presence of long-range spatial contacts for the segments containing methionines in this intrinsically disordered protein.