Mechanistic Insights into Neurotransmitter Release and Presynaptic Plasticity from the Crystal Structure of Munc13-1 C1C2BMUN
- University of Texas Southwestern Medical Center, United States
- Charité-Universitätsmedizin Berlin, Germany
- Huazhong University of Science and Technology, China
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.
Data availability
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C1C2BMUN structurePublicly available at the Protein Data Bank (accession no: 5UE8).
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Refined MUN domain structurePublicly available at the Protein Data Bank (accession no: 5UF7).
Article and author information
Author details
Christian Rosenmund
Funding
National Institutes of Health (R35 NS097333)
- Josep Rizo
Welch Foundation (I-1304)
- Josep Rizo
German Research Council (SFB958)
- Christian Rosenmund
German Research Council (SFB665)
- Christian Rosenmund
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Reinhard Jahn, Max Planck Institute for Biophysical Chemistry, Germany
Ethics
Animal experimentation: Animal welfare committees of Charité Medical University and the Berlin state government Agency for Health and Social Services approved all protocols for animal maintenance and experiments (license no. T 0220/09).
Version history
- Received: October 21, 2016
- Accepted: February 7, 2017
- Accepted Manuscript published: February 8, 2017 (version 1)
- Version of Record published: March 9, 2017 (version 2)
Copyright
© 2017, Xu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Mechanistic Insights into Neurotransmitter Release and Presynaptic Plasticity from the Crystal Structure of Munc13-1 C1C2BMUN
eLife 6:e22567.
https://doi.org/10.7554/eLife.22567
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