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 C1, C2B and MUN domains (C1C2BMUN) reveals a 19.5 nm-long multi-helical structure with the C1and C2B domains packed at one end. The similar orientations of the respective diacyglycerol- and Ca2+-binding sites of the C1and 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.
Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States.|Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, United States.|Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States.
Junjie
J
Xu
Department of Neurophysiology, NeuroCure Cluster of Excellence, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Marcial
M
Camacho
Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States.|Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, United States.|Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States.
Yibin
Y
Xu
Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States.|Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, United States.|Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States.
Victoria
V
Esser
Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States.|Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, United States.|Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States.
Xiaoxia
X
Liu
Department of Neurophysiology, NeuroCure Cluster of Excellence, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Thorsten
T
Trimbuch
Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States.|Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, United States.|Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States.
Yun-Zu
YZ
Pan
Key Laboratory of Molecular Biophysics of the Ministry of Education, Huazhong University of Science and Technology, Wuhan, China.|College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
Cong
0000-0002-7814-0500
C
Ma
Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States.|Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, United States.
Diana R
0000-0002-7529-4643
DR
Tomchick
Department of Neurophysiology, NeuroCure Cluster of Excellence, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Christian
0000-0002-3905-2444
C
Rosenmund
Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States.|Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, United States.|Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States.
Josep
0000-0003-1773-8311
J
Rizo
D000818:Animals; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D051379:Mice; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism*; D009474:Neurons / Q000502:physiology; D018377:Neurotransmitter Agents / Q000378:metabolism*; D011487:Protein Conformation; D051381:Rats
D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; C503321:Unc13a protein, mouse
Munc13; biophysics; calcium binding; mouse; neuroscience; neurotransmitter release; presynaptic plasticity; structural biology; synaptic vesicle fusion