Differences in the Binding of Copper(I) to α- and β-Synuclein

Parkinsons disease (PD) is a neurodegenerative disorder characterized by the presence of abnormal alpha-synuclein (alpha S) deposits in the brain. Alterations in homeostasis and metal-induced oxidative stress may play a crucial role in the progression of alpha S amyloid assembly and pathogenesis of PD. Contrary to alpha S, beta-synuclein (beta S) is not involved in the PD etiology. However, it has been suggested that the beta S/alpha S ratio is altered in PD, indicating that a correct balance of these two proteins is implicated in the inhibition of alpha S aggregation. alpha S and beta S share similar abilities to coordinate Cu(II). In this study, we investigated and compared the interaction of Cu(I) with the N-terminal portion of beta S and alpha S by means of NMR, circular dichroism, and X-ray absorption spectroscopies. Our data show the importance of M10K mutation, which induces different Cu(I) chemical environments. Coordination modes 3S1O and 2S2O were identified for beta S and alpha S, respectively. These new insights into the bioinorganic chemistry of copper and synuclein proteins are a basis to understand the molecular mechanism by which beta S might inhibit alpha S aggregation.