How Synaptotagmin Promotes Membrane Fusion

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Abstract
Synaptic vesicles loaded with neurotransmitters are exocytosed in a soluble N -ethylmaleimide–sensitive factor attachment protein receptor (SNARE)–dependent manner after presynaptic depolarization induces calcium ion (Ca 2+ ) influx. The Ca 2+ sensor required for fast fusion is synaptotagmin-1. The activation energy of bilayer-bilayer fusion is very high (≈40 k B T ). We found that, in response to Ca 2+ binding, synaptotagmin-1 could promote SNARE-mediated fusion by lowering this activation barrier by inducing high positive curvature in target membranes on C2-domain membrane insertion. Thus, synaptotagmin-1 triggers the fusion of docked vesicles by local Ca 2+ -dependent buckling of the plasma membrane together with the zippering of SNAREs. This mechanism may be widely used in membrane fusion.