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Title: 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.

Authors:
 [1];  [2];  [1];  [1];  [1];  [2];  [1]; ORCiD logo [3]; ORCiD logo [4]; ORCiD logo [2]; ORCiD logo [1]
  1. 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
  2. Department of Neurophysiology, NeuroCure Cluster of Excellence, Charité-Universitätsmedizin Berlin, Berlin, Germany
  3. 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
  4. Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, United States
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
NIHFOREIGNOTHER
OSTI Identifier:
1498359
Resource Type:
Journal Article
Journal Name:
eLife
Additional Journal Information:
Journal Volume: 6; Journal Issue: 02, 2017; Journal ID: ISSN 2050-084X
Publisher:
eLife Sciences Publications, Ltd.
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Xu, Junjie, Camacho, Marcial, Xu, Yibin, Esser, Victoria, Liu, Xiaoxia, Trimbuch, Thorsten, Pan, Yun-Zu, Ma, Cong, Tomchick, Diana R., Rosenmund, Christian, and Rizo, Josep. Mechanistic insights into neurotransmitter release and presynaptic plasticity from the crystal structure of Munc13-1 C1C2BMUN. United States: N. p., 2017. Web. doi:10.7554/eLife.22567.
Xu, Junjie, Camacho, Marcial, Xu, Yibin, Esser, Victoria, Liu, Xiaoxia, Trimbuch, Thorsten, Pan, Yun-Zu, Ma, Cong, Tomchick, Diana R., Rosenmund, Christian, & Rizo, Josep. Mechanistic insights into neurotransmitter release and presynaptic plasticity from the crystal structure of Munc13-1 C1C2BMUN. United States. doi:10.7554/eLife.22567.
Xu, Junjie, Camacho, Marcial, Xu, Yibin, Esser, Victoria, Liu, Xiaoxia, Trimbuch, Thorsten, Pan, Yun-Zu, Ma, Cong, Tomchick, Diana R., Rosenmund, Christian, and Rizo, Josep. Wed . "Mechanistic insights into neurotransmitter release and presynaptic plasticity from the crystal structure of Munc13-1 C1C2BMUN". United States. doi:10.7554/eLife.22567.
@article{osti_1498359,
title = {Mechanistic insights into neurotransmitter release and presynaptic plasticity from the crystal structure of Munc13-1 C1C2BMUN},
author = {Xu, Junjie and Camacho, Marcial and Xu, Yibin and Esser, Victoria and Liu, Xiaoxia and Trimbuch, Thorsten and Pan, Yun-Zu and Ma, Cong and Tomchick, Diana R. and Rosenmund, Christian and Rizo, Josep},
abstractNote = {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 = {10.7554/eLife.22567},
journal = {eLife},
issn = {2050-084X},
number = 02, 2017,
volume = 6,
place = {United States},
year = {2017},
month = {2}
}

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