Membrane packing defects in synaptic vesicles recruit complexin and synuclein

Complexin-1 (Cpx) and alpha-synuclein (alpha-Syn) are involved in neurotransmitter release through an interaction with synaptic vesicles (SVs). Recent studies demonstrated that Cpx and alpha-Syn preferentially associate with highly curved membranes, like SVs, to correctly position them for fusion. Here, based on recent experimental results, to further propose a possible explanation for this mechanism, we performed in silico simulations probing interactions between Cpx or alpha-Syn and membranes of varying curvature. We found that the preferential association is attributed to smaller, curved membranes containing more packing defects that expose hydrophobic acyl tails, which may favorably interact with hydrophobic residues of Cpx and alpha-Syn. The number of membrane defects is proportional to the curvature and the size can be regulated by cholesterol.