α-Synuclein cooperative binding to lipid membranes is a robust property over a wide range of conditions

Cooperativity is an efficient way for nature to regulate complex processes, allowing for control over a narrower range of concentrations compared to noncooperative phenomena. Here, we investigate the cooperative binding of α-Synuclein to lipid membranes under different conditions, aiming to uncover the underlying molecular driving forces. We interrogate the role of electrostatic interactions by rationally tuning α-Synuclein charge and the range of electrostatic interactions through variation in pH and ionic strength. To explore potential physiological and pathological implications, we also examine the cooperative binding of the H50Q mutant, which is linked to early-onset Parkinson’s disease. Using a multi-technique approach, we show that cooperativity is a robust property of α-Synuclein binding to anionic membranes, persisting in both the wild-type and mutant proteins. Our findings reveal that membrane-mediated effects, rather than electrostatics or direct protein-protein interactions, could be the main driving forces underlying this strong cooperativity.