TCB Publications - Abstract

TCB Publications - Abstract

Zhe Wu and Klaus Schulten. Synaptotagmin's role in neurotransmitter release likely involves Ca2+-induced conformational transition. Biophysical Journal, 107:1156-1166, 2014. (PMC: PMC4156666)

WU2014 Neuronal exocytosis is mediated by a Ca$^{2+}$-triggered membrane fusion event that joins synaptic vesicles and presynaptic membrane. In this event, synaptotagmin I plays a key role as a Ca$^{2+}$ sensor protein that binds to and bends the presynaptic membrane with its C2B domain and, thereby, initiates membrane fusion. We report free energy calculations according to which C2B-induced membrane bending is preceded by a significant Ca$^{2+}$- and membrane-dependent conformational transition. In this transition C2B attaches to the membrane, moves its C-terminal helix from the orientation seen in the available, but 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 monitored in the simulations is well suited to facilitate Ca$^{2+}$-triggered membrane fusion.

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