Mechanistic Insights into Neurotransmitter Release and Presynaptic Plasticity from the Crystal Structure of Munc13-1 C1C2BMUN

  1. Junjie Xu
  2. Marcial Camacho
  3. Yibin Xu
  4. Vicotoria Esser
  5. Xiaoxia Liu
  6. Thorsten Trimbuch
  7. Yun-Zu Pan
  8. Cong Ma
  9. Diana R Tomchick  Is a corresponding author
  10. Christian Rosenmund  Is a corresponding author
  11. Josep Rizo  Is a corresponding author
  1. University of Texas Southwestern Medical Center, United States
  2. Charité-Universitätsmedizin Berlin, Germany
  3. 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

The following data sets were generated
    1. Rizo et al.
    (2016) C1C2BMUN structure
    Publicly available at the Protein Data Bank (accession no: 5UE8).
    1. Rizo et al.
    (2016) Refined MUN domain structure
    Publicly available at the Protein Data Bank (accession no: 5UF7).

Article and author information

Author details

  1. Junjie Xu

    Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  2. Marcial Camacho

    Department of Neurophysiology, Charité-Universitätsmedizin Berlin, Berlin, Germany
    Competing interests
    No competing interests declared.
  3. Yibin Xu

    Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  4. Vicotoria Esser

    Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  5. Xiaoxia Liu

    Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  6. Thorsten Trimbuch

    Department of Neurophysiology, Charité-Universitätsmedizin Berlin, Berlin, Germany
    Competing interests
    No competing interests declared.
  7. Yun-Zu Pan

    Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  8. Cong Ma

    Key Laboratory of Molecular Biophysics of the Ministry of Education, Huazhong University of Science and Technology, Wuhan, China
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7814-0500
  9. Diana R Tomchick

    Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    diana.tomchick@utsouthwestern.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7529-4643
  10. Christian Rosenmund

    Department of Neurophysiology, Charité-Universitätsmedizin Berlin, Berlin, Germany
    For correspondence
    christian.rosenmund@charite.de
    Competing interests
    Christian Rosenmund, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3905-2444
  11. Josep Rizo

    Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    Jose.Rizo-Rey@UTSouthwestern.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1773-8311

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

  1. 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

  1. Received: October 21, 2016
  2. Accepted: February 7, 2017
  3. Accepted Manuscript published: February 8, 2017 (version 1)
  4. 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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  1. Junjie Xu
  2. Marcial Camacho
  3. Yibin Xu
  4. Vicotoria Esser
  5. Xiaoxia Liu
  6. Thorsten Trimbuch
  7. Yun-Zu Pan
  8. Cong Ma
  9. Diana R Tomchick
  10. Christian Rosenmund
  11. Josep Rizo
(2017)
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

Share this article

https://doi.org/10.7554/eLife.22567

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