Abstract
Munc13-1 plays a crucial role in neurotransmitter release. We recently proposed that the C-terminal region encompassing the C
, C
B, MUN and C
C domains of Munc13-1 (C
C
BMUNC
C) bridges the synaptic vesicle and plasma membranes through interactions involving the C
C domain and the C
-C
B region. However, the physiological relevance of this model has not been demonstrated. Here we show that C
C
BMUNC
C bridges membranes through opposite ends of its elongated structure. Mutations in putative membrane-binding sites of the C
C domain disrupt the ability of C
C
BMUNC
C to bridge liposomes and to mediate liposome fusion in vitro. These mutations lead to corresponding disruptive effects on synaptic vesicle docking, priming, and Ca
-triggered neurotransmitter release in mouse neurons. Remarkably, these effects include an almost complete abrogation of release by a single residue substitution in this 200 kDa protein. These results show that bridging the synaptic vesicle and plasma membranes is a central function of Munc13-1.