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

Abstract

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 C₁, C₂B and MUN domains (C₁C₂BMUN) reveals a 19.5 nm-long multi-helical structure with the C₁ and C₂B domains packed at one end. The similar orientations of the respective diacyglycerol- and Ca²⁺-binding sites of the C₁ 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.