Synaptotagmin has been proposed to function as a Ca²⁺ sensor that regulates synaptic vesicle exocytosis, whereas the solubleN-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex is thought to form the core of a conserved membrane fusion machine. Little is known concerning the functional relationships between synaptotagmin and SNAREs. Here we report that synaptotagmin can facilitate SNARE complex formationin vitro and that synaptotagmin mutations disrupt SNARE complex formation in vivo. Synaptotagmin oligomers efficiently bind SNARE complexes, whereas Ca²⁺ acting via synaptotagmin triggers cross-linking of SNARE complexes into dimers. Mutations in Drosophilathat delete the C2B domain of synaptotagmin disrupt clathrin AP-2 binding and endocytosis. In contrast, a mutation that blocks Ca²⁺-triggered conformational changes in C2B and diminishes Ca²⁺-triggered synaptotagmin oligomerization results in a postdocking defect in neurotransmitter release and a decrease in SNARE assembly in vivo. These data suggest that Ca²⁺-driven oligomerization via the C2B domain of synaptotagmin may trigger synaptic vesicle fusion via the assembly and clustering of SNARE complexes.
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Littleton et al. (2001) studied this question.