Mechanistic insights into neurotransmitter release and presynaptic plasticity from the crystal structure of Munc13-1 C1C2BMUN

Munc13-1 acts as a master regulator of neurotransmitter release, mediating docking-priming of synaptic vesicles and diverse presynaptic plasticity processes. It is unclear how the functions of the multiple domains of Munc13-1 are coordinated. The crystal structure of a Munc13-1 fragment including its C-1, C2B and MUN domains (C1C2BMUN) reveals a 19.5 nm-long multihelical structure with the C-1 and C2B domains packed at one end. The similar orientations of the respective diacyglycerol- and Ca2+-binding sites of the C-1 and C2B domains suggest that the two domains cooperate in plasma-membrane binding and that activation of Munc13-1 by Ca2+ and diacylglycerol during short-term presynaptic plasticity are closely interrelated. Electrophysiological experiments in mouse neurons support the functional importance of the domain interfaces observed in C1C2BMUN. The structure imposes key constraints for models of neurotransmitter release and suggests that Munc13-1 bridges the vesicle and plasma membranes from the periphery of the membrane-membrane interface.