C2B Domain in Synaptotagmin I Induces Membrane Bending Only After Conformational Change

Abstract

Neuronal exocytosis is mediated by a Ca2+-triggered membrane fusion event that joins synaptic vesicles and presynaptic membrane. In this event, synaptotagmin I plays a key role as a Ca2+ sensor protein that binds to and bends the presynaptic membrane with its C2B domain and, thereby, triggers membrane fusion. We report free energy calculations according to which C2B-induced membrane bending is preceded by a Ca2+- and membrane-dependent conformational transition, in which C2B attaches to the membrane, moves its C-terminal helix from the orientation seen in the membrane-free crystal/NMR structures as pointing away from the membrane (helix up), to an orientation pointing towards the membrane (helix down). In the C2B “helix down” state, lipid tails in the proximal membrane bilayer leaflet interact with the moved helix and become disordered, while tails in the distal leaflet, to keep in contact with the proximal leaflet, become stretched and ordered. The difference in lipid tail packing between the two leaflets results in an imbalance of pressure across the membrane and, thereby, causes membrane bending. The lipid disordering in the proximal membrane leaflet should facilitate Ca2+-triggered membrane fusion.