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The Journal of Neuroscience, March 1, 2001, 21(5):1421-1433
synaptotagmin Mutants Reveal Essential Functions for the C2B Domain in Ca2+-Triggered Fusion and Recycling of Synaptic Vesicles In Vivo
J. Troy Littleton4, Jihong Bai1, Bimal Vyas1, Radhika Desai1, Andrew E. Baltus4, Martin B. Garment2, Stanley D. Carlson2, Barry Ganetzky3, and Edwin R. Chapman1 Departments of 1 Physiology and 2 Entomology, and 3 Laboratory of Genetics, University of Wisconsin, Madison, Wisconsin 53706, and 4 Center for Learning and Memory and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Synaptotagmin has been proposed to function as a Ca2+ sensor that regulates synaptic vesicle exocytosis, whereas the soluble N-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 formation in 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 Drosophila that 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.
Key words: exocytosis; synaptotagmin; SNARE; Ca2+; synaptic vesicle; membrane fusion; C2 domain; Drosophila
Copyright © 2001 Society for Neuroscience 0270-6474/01/2151421-13$05.00/0
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