title: Conformational change of syntaxin linker region induced by Munc13s initiates SNARE complex formation in synaptic exocytosis.
abstract: The soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein syntaxin-1 adopts a closed conformation when bound to Munc18-1, preventing binding to synaptobrevin-2 and SNAP-25 to form the ternary SNARE complex. Although it is known that the MUN domain of Munc13-1 catalyzes the transition from the Munc18-1/syntaxin-1 complex to the SNARE complex, the molecular mechanism is unclear. Here, we identified two conserved residues (R151, I155) in the syntaxin-1 linker region as key sites for the MUN domain interaction. This interaction is essential for SNARE complex formationin vitroand synaptic vesicle priming in neuronal cultures. Moreover, this interaction is important for a tripartite Munc18-1/syntaxin-1/MUN complex, in which syntaxin-1 still adopts a closed conformation tightly bound to Munc18-1, whereas the syntaxin-1 linker region changes its conformation, similar to that of the LE mutant of syntaxin-1 when bound to Munc18-1. We suggest that the conformational change of the syntaxin-1 linker region induced by Munc13-1 initiates ternary SNARE complex formation in the neuronal system.
authors.affiliation: Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology and the Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Shen
authors.identifier: 0000-0002-5013-1039
authors.initials: S
authors.lastname: Wang
authors.affiliation: Departments of Molecular and Cellular Physiology, Neurology and Neurological Sciences, Photon Science, and Structural Biology, Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA.
authors.forename: Ucheor B
authors.initials: UB
authors.lastname: Choi
authors.affiliation: Key Laboratory of Cognitive Science, Hubei Key Laboratory of Medical Information Analysis and Tumor Diagnosis & Treatment, Laboratory of Membrane Ion Channels and Medicine, College of Biomedical Engineering, College of Life Science, South-Central University for Nationalities, Wuhan, China.
authors.forename: Jihong
authors.initials: J
authors.lastname: Gong
authors.affiliation: Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology and the Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Yang
authors.affiliation: Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology and the Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.affiliation: Departments of Molecular and Cellular Physiology, Neurology and Neurological Sciences, Photon Science, and Structural Biology, Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA.
authors.forename: Austin L
authors.initials: AL
authors.lastname: Wang
authors.affiliation: Key Laboratory of Cognitive Science, Hubei Key Laboratory of Medical Information Analysis and Tumor Diagnosis & Treatment, Laboratory of Membrane Ion Channels and Medicine, College of Biomedical Engineering, College of Life Science, South-Central University for Nationalities, Wuhan, China sunlittlefly@hotmail.com brunger@stanford.edu cong.ma@hust.edu.cn.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Yang
authors.affiliation: Departments of Molecular and Cellular Physiology, Neurology and Neurological Sciences, Photon Science, and Structural Biology, Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA sunlittlefly@hotmail.com brunger@stanford.edu cong.ma@hust.edu.cn.
authors.forename: Axel T
authors.initials: AT
authors.lastname: Brunger
authors.affiliation: Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology and the Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, China sunlittlefly@hotmail.com brunger@stanford.edu cong.ma@hust.edu.cn.
authors.forename: Cong
authors.identifier: 0000-0002-7814-0500
authors.initials: C
authors.lastname: Ma
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005089:Exocytosis; D006801:Humans; D008954:Models, Biological; D051938:Munc18 Proteins / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000502:physiology*; D011487:Protein Conformation; D050765:Qa-SNARE Proteins / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D050600:SNARE Proteins / Q000378:metabolism*; D013569:Synapses / Q000502:physiology*
chemical_list: D051938:Munc18 Proteins; D009419:Nerve Tissue Proteins; D050765:Qa-SNARE Proteins; D050600:SNARE Proteins; C497939:Stxbp1 protein, rat; C103912:Unc13a protein, rat
keywords: Munc13; Munc18; neurotransmitter release; synaptic vesicle fusion; syntaxin