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Cited by 119Cellular transport and secretionNeuroscience and Neuropharmacology ResearchProtein Kinase Regulation and GTPase Signaling

Mechanistic insights into neurotransmitter release and presynaptic plasticity from the crystal structure of Munc13-1 C1C2BMUN

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Xu, Junjie, Camacho, Marcial, Xu, Yibin, Esser, Victoria, Liu, Xiaoxia, Trimbuch, Thorsten, Pan, Yun-Zu, Ma, Cong +3 more·2017·eLife
DOI 10.7554/elife.22567PMC PMC5344669
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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.

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  • PKC, Munc13 and RasGRP4 are regulated by transient changes in DAG.

    “Members of the PKC and Munc13 (mammalian uncoordinated-13) family as well as RasGRP4 (Ras guanyl-releasing protein 4) are prime examples of proteins that are regulated by transient changes in DAG [51–53].”

    From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [52]

    The Discussion (page not provided) describes Munc13-1 activation by increased DAG during repetitive stimulation, supporting the Munc13 part of the sentence. The passages do not address DAG regulation of PKC or RasGRP4, so this source does not support those parts of the combined claim. (LLM, conf=0.86)

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Cited by

Sorted by citations

Authors
Xu, J., Camacho, M., Xu, Y., Esser, V., Liu, X., Trimbuch, T., Pan, Y.-Z., Ma, C., Tomchick, D. R., Rosenmund, C., & Rizo, J.
Affiliations
  • The University of Texas Southwestern Medical Center (US)
  • NeuroCure Cluster of Excellence (DE)
  • Huazhong University of Science and Technology (CN)
Corresponding author
  • Tomchick, Diana R
  • Rosenmund, Christian
  • Rizo, Josep
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2017-02-08
Volume
6
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.22567
PMC
PMC5344669
OpenAlex
W2587405972
Cited by
119
References
7
Citations by year
2026: 6 · 2025: 12 · 2024: 5 · 2023: 11 · 2022: 19 · 2021: 15 · 2020: 13 · 2019: 14 · 2018: 10 · 2017: 13 · 2014: 1
FWCI
7.30
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Deutsche Forschungsgemeinschaft (SFB958, SFB665)
  • National Institutes of Health (R35 NS097333, NS037200, NS049044)
  • Welch Foundation (I-1304)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
Munc13-1, neurotransmitter release, presynaptic plasticity, synaptic vesicle docking, C1 domain, C2B domain, calcium binding, plasma membrane binding, short-term plasticity
MeSH terms
Animals, Cells, Cultured, Models, Molecular, Nerve Tissue Proteins, Neurons, Protein Conformation, Crystallography, X-Ray, Neurotransmitter Agents, Mice, Rats

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