Structural Basis for a Munc13–1 Homodimer to Munc13–1/RIM Heterodimer Switch
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C(2) domains are well characterized as Ca(2+)/phospholipid-binding modules, but little is known about how they mediate protein-protein interactions. In neurons, a Munc13-1 C(2)A-domain/RIM zinc-finger domain (ZF) heterodimer couples synaptic vesicle priming to presynaptic plasticity. We now show that the Munc13-1 C(2)A domain homodimerizes, and that homodimerization competes with Munc13-1/RIM heterodimerization. X-ray diffraction studies guided by nuclear magnetic resonance (NMR) experiments reveal the crystal structures of the Munc13-1 C(2)A-domain homodimer and the Munc13-1 C(2)A-domain/RIM ZF heterodimer at 1.44 A and 1.78 A resolution, respectively. The C(2)A domain adopts a beta-sandwich structure with a four-stranded concave side that mediates homodimerization, leading to the formation of an eight-stranded beta-barrel. In contrast, heterodimerization involves the bottom tip of the C(2)A-domain beta-sandwich and a C-terminal alpha-helical extension, which wrap around the RIM ZF domain. Our results describe the structural basis for a Munc13-1 homodimer-Munc13-1/RIM heterodimer switch that may be crucial for vesicle priming and presynaptic plasticity, uncovering at the same time an unexpected versatility of C(2) domains as protein-protein interaction modules, and illustrating the power of combining NMR spectroscopy and X-ray crystallography to study protein complexes.
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RIM1/2 recruits Munc13-1s to active zones and interacts with other active zone components to enable exocytosis.
“RIM1/2 recruits Munc13-1s to AZs [72,73] and interacts with other AZ components to enable exocytosis [73–76].”
From Presynaptic cAMP-PKA-mediated potentiation induces reconfiguration of synaptic vesicle pools and channel-vesicle coupling at hippocampal mossy fiber boutons (2024) · cites this paper as [72]
The Introduction reports that Munc13-1 binds RIM1α/RIM2α at active zones and that disrupting this interaction impairs vesicle priming. Biological Implications describes RIM interactions with Rab3A that may help couple priming to the release machinery. These passages support a role in exocytosis, but do not establish that RIM1/2 recruits Munc13-1 to active zones. (LLM, conf=0.78)
Experimental — accuracy not yet measuredThe C2A domain of Munc13-1 interacts with the zinc-finger domain of RIM building a heterodimeric complex.
“In contrast, the C2A domain of Munc13-1 interacts with the zinc-finger domain of RIM building a heterodimeric complex [72,89–91].”
From Presynaptic cAMP-PKA-mediated potentiation induces reconfiguration of synaptic vesicle pools and channel-vesicle coupling at hippocampal mossy fiber boutons (2024) · cites this paper as [72]
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- Authors
- Lu, J., Machius, M., Dulubova, I., Dai, H., Südhof, T. C., Tomchick, D. R., & Rizo, J.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Rizo, Josep
- Venue
- PLoS Biology
- Publisher
- Public Library of Science (PLoS)
- Published
- 2006-06-06
- Volume
- 4
- Issue
- 7
- Pages
- e192
- ISSN
- 1544-9173 (ISSN-L)
- 1545-7885
- PMC
- PMC1472246
- OpenAlex
- W2125339888
- Cited by
- 132
- References
- 45
- Citations by year
- 2026: 1 · 2025: 12 · 2024: 4 · 2023: 10 · 2022: 9 · 2021: 3 · 2020: 3 · 2019: 8 · 2018: 8 · 2017: 13 · 2016: 2 · 2015: 4 · 2014: 7 · 2013: 8 · 2012: 7
- FWCI
- 2.35
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Biology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- U.S. Department of Energy (31-109-ENG-38, W - 31 - 109 - Eng - 38)
- American Heart Association
- National Institutes of Health (W-31-109-ENG-38)
- National Institute of Neurological Disorders and Stroke (NS40944, R01NS040944)
- Biological and Environmental Research (W-31-109-ENG, W-31-109-ENG-38)
- Argonne National Laboratory (W-31-109-ENG-38, W-31-109, ENG-38)
- 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, homodimerization, heterodimerization, protein-protein interaction, synaptic vesicle priming, presynaptic plasticity, beta-sandwich structure, beta-barrel, synaptotagmin, crystal structure
- MeSH terms
- Amino Acid Sequence, Animals, Models, Molecular, Molecular Sequence Data, Nerve Tissue Proteins, Magnetic Resonance Spectroscopy, Protein Binding, Protein Conformation, Synaptic Vesicles, Zinc Fingers, Sequence Alignment, Protein Structure, Tertiary, Crystallography, X-Ray, Dimerization, Protein Interaction Mapping, Rats
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