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

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. DOI: http://dx.doi.org/10.7554/eLife.22567.001
eLife digest The human brain contains billions of cells called neurons that communicate with each other using molecules called neurotransmitters. An electrical signal in one neuron triggers the release of neurotransmitters from the cell, which then activate or inhibit electrical signals in neighboring neurons. Inside the cell, neurotransmitters are stored in small bubble-like structures called synaptic vesicles. The vesicles fuse with the membrane that surrounds the cell to release the neurotransmitters. This process must be tightly controlled to ensure that neurotransmitters are released rapidly and at the right time. A protein called Munc13 is a key component of the machinery that regulates the fusion of synaptic vesicles. It helps the synaptic vesicle to dock onto the cell membrane and get ready for fusion. Munc13 is a large protein and contains several different regions, including three domains called C1, C2B and MUN. These three domains control the release of neurotransmitters, but how they do so is poorly understood. Xu, Camacho et al. used a technique called X-ray crystallography to analyse the three-dimensional shape of the part of Munc13 that contains the three domains. The experiments reveal that the MUN domain forms a long rod-like shape with the C1 and C2B domains packed at one end. Several mutations that reduce the ability of the domains to interact with each other altered the release of neurotransmitters from mouse neurons to different extents. These findings suggest that the overall architecture of the region containing the C1, C2B and MUN domains is important for the normal activity of Munc13. The structure revealed by Xu, Camacho et al. sets a framework for understanding how Munc13 controls neurotransmitter release, and thus mediates diverse forms of information processing in the brain. DOI: http://dx.doi.org/10.7554/eLife.22567.002