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Munc13 mediates the transition from the closed syntaxin–Munc18 complex to the SNARE complex

Nature Structural & Molecular Biology volume 18, pages 542–549 (2011)Cite this article

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Abstract

During the priming step that leaves synaptic vesicles ready for neurotransmitter release, the SNARE syntaxin-1 transitions from a closed conformation that binds Munc18-1 tightly to an open conformation within the highly stable SNARE complex. Control of this conformational transition is important for brain function, but the underlying mechanism is unknown. NMR and fluorescence experiments now show that the Munc13-1 MUN domain, which plays a central role in vesicle priming, markedly accelerates the transition from the syntaxin-1–Munc18-1 complex to the SNARE complex. This activity depends on weak interactions of the MUN domain with the syntaxin-1 SNARE motif, and probably with Munc18-1. Together with available physiological data, these results provide a defined molecular basis for synaptic vesicle priming, and they illustrate how weak protein-protein interactions can play crucial biological roles by promoting transitions between high-affinity macromolecular assemblies.

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Figure 1: Weak interactions can dramatically accelerate transitions between tight complexes.
Figure 2: Formation of MUN*–SNARE complex–Munc18-1 macromolecular assemblies.
Figure 3: MUN* binds to the syntaxin-1 SNARE motif.
Figure 4: The MUN domain accelerates the transition from the syntaxin-1–Munc18-1 complex to the SNARE complex.
Figure 5: MUN* activity depends on interactions with the syntaxin-1 SNARE motif and is bypassed by the syntaxin-1 LE mutation.

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Acknowledgements

We thank Y. Sun of the University of Texas Southwestern Medical Center (UT Southwestern) for expert technical assistance, Y. Xu and L. Su (UT Southwestern) for fruitful discussions, M. Rosen (UT Southwestern) and L. Kay (University of Toronto) for advice on NMR experiments and W. Wickner (Dartmouth University) for insightful comments on the manuscript. This work was supported by a postdoctoral fellowship from the American Heart Association (to Y.X.), by Welch foundation grant I-1304 and by US National Institutes of Health grant NS37200 (both to J.R.).

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  1. Cong Ma and Wei Li: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Cong Ma, Wei Li, Yibin Xu & Josep Rizo

  2. Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Cong Ma, Wei Li, Yibin Xu & Josep Rizo

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  1. Cong Ma
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Contributions

C.M. did the kinetic studies of SNARE complex formation. C.M., W.L. and J.R. conducted the NMR experiments. Y.X. did initial biochemical studies of the MUN domain. J.R. wrote the paper.

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Correspondence to Josep Rizo.

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Ma, C., Li, W., Xu, Y. et al. Munc13 mediates the transition from the closed syntaxin–Munc18 complex to the SNARE complex. Nat Struct Mol Biol 18, 542–549 (2011). https://doi.org/10.1038/nsmb.2047

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