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

α-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 α-synuclein and modulate its aggregation propensity and toxicity. However, the synergistic effect of copper ions and lipid membranes on α-synuclein remains to be explored. Here, we investigate how Cu²⁺ and α-synuclein simultaneously influence the lipidic structure of lipidic cubic phase(LCP) matrix by using small-angle X-ray scattering. α-Syn proteins destabilize the cubic-Pn3m phase of LCP that can be further recovered after the addition of Cu² 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 α-synuclein at an atomic level. Although the secondary structure of α-synuclein with lipid membranes is not significantly changed to a large extent in the presence of Cu²⁺ ions, lipid membranes promote the interaction between α-synuclein C-terminus and Cu²⁺ ions. The modulation of Cu²⁺ ions and lipid membranes on α-synuclein dynamics and structure may play an important role in the molecular pathogenesis of Parkinson's disease.