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

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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).

http://www.rcsb.org/pdb/explore/explore.do?structureId=5UE8
1. Rizo et al.
(2016) Refined MUN domain structure
Publicly available at the Protein Data Bank (accession no: 5UF7).

http://www.rcsb.org/pdb/explore/explore.do?structureId=5UF7

Article and author information

Author details

Junjie Xu

Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
No competing interests declared.
Marcial Camacho

Department of Neurophysiology, Charité-Universitätsmedizin Berlin, Berlin, Germany

Competing interests
No competing interests declared.
Yibin Xu

Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
No competing interests declared.
Vicotoria Esser

Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
No competing interests declared.
Xiaoxia Liu

Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
No competing interests declared.
Thorsten Trimbuch

Department of Neurophysiology, Charité-Universitätsmedizin Berlin, Berlin, Germany

Competing interests
No competing interests declared.
Yun-Zu Pan

Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
No competing interests declared.
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.

"This ORCID iD identifies the author of this article:" 0000-0002-7814-0500
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.

"This ORCID iD identifies the author of this article:" 0000-0002-7529-4643
Christian Rosenmund

Department of Neurophysiology, Charité-Universitätsmedizin Berlin, Berlin, Germany

For correspondence
christian.rosenmund@charite.de

Competing interests
Christian Rosenmund, Reviewing editor, eLife.

"This ORCID iD identifies the author of this article:" 0000-0002-3905-2444
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.

"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.

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).

Copyright

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.