Phosphatidylserine-dependent structure of synaptogyrin remodels the synaptic vesicle membrane

Synaptic vesicles are small membrane-enclosed organelles that store neurotransmitters at presynaptic terminals. The uniform morphology of synaptic vesicles is important for brain function, because it enables the storage of well-defined amounts of neurotransmitters and thus reliable synaptic transmission. Here, we show that the synaptic vesicle membrane protein synaptogyrin cooperates with the lipid phosphatidylserine to remodel the synaptic vesicle membrane. Using NMR spectroscopy, we determine the high-resolution structure of synaptogyrin and identify specific binding sites for phosphatidylserine. We further show that phosphatidylserine binding changes the transmembrane structure of synaptogyrin and is critical for membrane bending and the formation of small vesicles. Cooperative binding of phosphatidylserine to both a cytoplasmic and intravesicular lysine-arginine cluster in synaptogyrin is required for the formation of small vesicles. Together with other synaptic vesicle proteins, synaptogyrin thus can sculpt the membrane of synaptic vesicles.