Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 15, Issue 8, Pages 827-835Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.1463
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Funding
- Howard Hughes Medical Institute Funding Source: Medline
- NIGMS NIH HHS [R01 GM056827-09, R01 GM056827] Funding Source: Medline
- NIMH NIH HHS [R01 MH061876-06, R01 MH061876] Funding Source: Medline
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Neuronal communication is mediated by Ca(2+)-triggered fusion of transmitter-filled synaptic vesicles with the presynaptic plasma membrane. Synaptotagmin I functions as a Ca(2+) sensor that regulates exocytosis, whereas soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptor (SNARE) proteins in the vesicle and target membrane assemble into complexes that directly catalyze bilayer fusion. Here we report that, before the Ca(2+) trigger, synaptotagmin interacts with SNARE proteins in the target membrane to halt SNARE complex assembly at a step after donor vesicles attach, or dock, to target membranes. This results in fusion complexes that, when subsequently triggered by Ca(2+), drive rapid, highly efficient lipid mixing. Ca(2+)-independent interactions with SNAREs also predispose synaptotagmin to selectively penetrate the target membrane in response to Ca(2+); we demonstrate that Ca(2+)-synaptotagmin must insert into the target membrane to accelerate SNARE-catalyzed fusion. These findings demonstrate that Ca(2+) converts synaptotagmin from a clamp to a trigger for exocytosis.
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