Cu2+ ions modulate the interaction between ?-synuclein and lipid membranes

alpha-synuclein protein aggregates are the major constituent of Lewy bodies, which is a main pathogenic hallmark of Parkinson's disease. Both lipid membranes and Cu2+ ions can bind to alpha-synuclein and modulate its aggregation propensity and toxicity. However, the synergistic effect of copper ions and lipid membranes on alpha-synuclein re-mains to be explored. Here, we investigate how Cu2+ and alpha-synuclein simultaneously influence the lipidic structure of lipidic cubic phase(LCP) matrix by using small-angle X-ray scattering. alpha-Syn proteins destabilize the cubic-Pn(3)m phase of LCP that can be further recovered after the addition of Cu-2 ions even at a low stoichiometric ratio. By using circular dichroism and nuclear magnetic resonance, we also study how lipid membranes and Cu2+ ions impact the secondary structures of alpha-synuclein at an atomic level. Although the secondary structure of alpha-synuclein with lipid membranes is not significantly changed to a large extent in the presence of Cu2+ ions, lipid membranes promote the interaction between alpha-synuclein C-terminus and Cu2+ ions. The modulation of Cu2+ ions and lipid membranes on alpha-synuclein dynamics and structure may play an important role in the molecular pathogenesis of Parkinson's disease.