Abstract
Neuronal SNAREs (synaptobrevin, syntaxin, SNAP-25), synaptotagmin, complexin, Munc13, and Munc18 are essential for fast Ca2+-triggered synaptic vesicle fusion. Syntaxin forms a closed complex with Munc18 that prevents SNARE complex formation, and Munc13 catalyzes the opening and transit of syntaxin into the SNARE complex. However, Munc13 knockout in mice cannot be fully rescued with a constitutively open mutant of syntaxin. We report a new function of Munc13, independent of Munc18: it promotes the proper syntaxin/synaptobrevin subconfiguration during assembly of the ternary SNARE complex. In cooperation with Munc18, Munc13 additionally ensures the proper syntaxin/SNAP-25 subconfiguration. In a reconstituted fusion assay with SNAREs, complexin, and synaptotagmin, inclusion of both Munc13 and Munc18 quadruples the Ca2+-triggered amplitude, and improves the Ca2+-sensitivity by an order of magnitude, reaching physiological sensitivity. If Munc13 or Munc18 is deleted, improperly assembled SNARE complexes may occur, explaining the observed abrogation of neurotransmitter release in neurons.
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