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Syntaxin opening by the MUN domain underlies the function of Munc13 in synaptic-vesicle priming

Journal Article · · Nature Structural & Molecular Biology
DOI:https://doi.org/10.1038/nsmb.3038· OSTI ID:1259896
 [1];  [1];  [1];  [2];  [3];  [4];  [3];  [5];  [6];  [7];  [1]
  1. Huazhong Univ. of Science and Technology, Wuhan (China)
  2. Chinese Academy of Sciences (CAS), Beijing (China)
  3. Zhejiang Univ., Hangzhou (China)
  4. Chinese Academy of Sciences (CAS), Shanghai (China)
  5. Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)
  6. Chinese Academy of Sciences (CAS), Beijing (China); Chinese Academy of Sciences (CAS), Shanghai (China)
  7. Huazhong Univ. of Science and Technology, Wuhan (China); Chinese Academy of Sciences (CAS), Beijing (China); Univ. of Chinese Academy of Sciences, Beijing (China)

UNC-13-Munc13s have a central function in synaptic-vesicle priming through their MUN domains. However, it is unclear whether this function arises from the ability of the MUN domain to mediate the transition from the Munc18-1–closed syntaxin-1 complex to the SNARE complex in vitro. The crystal structure of the rat Munc13-1 MUN domain now reveals an elongated, arch-shaped architecture formed by α-helical bundles, with a highly conserved hydrophobic pocket in the middle. Mutation of two residues (NF) in this pocket abolishes the stimulation caused by the Munc13-1 MUN domain on SNARE-complex assembly and on SNARE-dependent proteoliposome fusion in vitro. Moreover, the same mutation in UNC-13 abrogates synaptic-vesicle priming in Caenorhabditis elegans neuromuscular junctions. Here, these results support the notion that orchestration of syntaxin-1 opening and SNARE-complex assembly underlies the central role of UNC-13-Munc13s in synaptic-vesicle priming.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
National Science Foundation of China; National Key Basic Research Program of China; U.S. National Inst. of Health
OSTI ID:
1259896
Journal Information:
Nature Structural & Molecular Biology, Journal Name: Nature Structural & Molecular Biology Journal Issue: 7 Vol. 22; ISSN 1545-9993
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Sec3 promotes the initial binary t-SNARE complex assembly and membrane fusion journal January 2017
Munc18 and Munc13 serve as a functional template to orchestrate neuronal SNARE complex assembly journal January 2019
Munc18-1 is crucial to overcome the inhibition of synaptic vesicle fusion by αSNAP journal September 2019
OSM-9 and an amiloride-sensitive channel, but not PKD-2, are involved in mechanosensation in C. elegans male ray neurons journal May 2018
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Rare genetic variation in UNC13A may modify survival in amyotrophic lateral sclerosis journal September 2016
Correction: ELKS1 localizes the synaptic vesicle priming protein bMunc13-2 to a specific subset of active zones journal March 2017
Roles of the fission yeast UNC-13/Munc13 protein Ync13 in late stages of cytokinesis journal September 2018
Munc18-1 catalyzes neuronal SNARE assembly by templating SNARE association posted_content September 2018
Decoding the intensity of sensory input by two glutamate receptors in one C. elegans interneuron. journalarticle January 2018
A Systematic RNAi Screen Reveals a Novel Role of a Spindle Assembly Checkpoint Protein BuGZ in Synaptic Transmission in C. elegans journal May 2017
A Stimulation Function of Synaptotagmin-1 in Ternary SNARE Complex Formation Dependent on Munc18 and Munc13 journal August 2017
Additional file 3 of Identification of residues critical for the extension of Munc18-1 domain 3a dataset January 2023
Identification of a Munc13-sensitive step in chromaffin cell large dense-core vesicle exocytosis journal November 2015
Functional synergy between the Munc13 C-terminal C1 and C2 domains journal May 2016
Synaptotagmin-1 C2B domain interacts simultaneously with SNAREs and membranes to promote membrane fusion journal April 2016
Mechanistic insights into neurotransmitter release and presynaptic plasticity from the crystal structure of Munc13-1 C1C2BMUN journal February 2017
Autoinhibition of Munc18-1 modulates synaptobrevin binding and helps to enable Munc13-dependent regulation of membrane fusion journal May 2017
Multiple factors maintain assembled trans-SNARE complexes in the presence of NSF and αSNAP journal January 2019
Heterodimerization of UNC-13/RIM regulates synaptic vesicle release probability but not priming in C. elegans journal February 2019
Membrane bridging by Munc13-1 is crucial for neurotransmitter release journal February 2019
Hypothesis - buttressed rings assemble, clamp, and release SNAREpins for synaptic transmission journal October 2017
Tomosyn guides SNARE complex formation in coordination with Munc18 and Munc13 journal February 2018
Mechanism of neurotransmitter release coming into focus: Mechanism of Neurotransmitter Release journal July 2018
Intrinsic and extrinsic mechanisms of synapse formation and specificity in C. elegans journal April 2019
Serotonergic neuron ADF modulates avoidance behaviors by inhibiting sensory neurons in C. elegans journal September 2018
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Molecular mechanisms of contractile-ring constriction and membrane trafficking in cytokinesis journal November 2018
Simultaneous lipid and content mixing assays for in vitro reconstitution studies of synaptic vesicle fusion journal August 2017
Chaperoning SNARE assembly and disassembly journal June 2016
Decoding the intensity of sensory input by two glutamate receptors in one C. elegans interneuron journal October 2018
The control of release probability at nerve terminals journal January 2019
SNARE zippering requires activation by SNARE-like peptides in Sec1/Munc18 proteins journal August 2018
Munc13-1 MUN domain and Munc18-1 cooperatively chaperone SNARE assembly through a tetrameric complex journal December 2019
The Vesicle Priming Factor CAPS Functions as a Homodimer via C2 Domain Interactions to Promote Regulated Vesicle Exocytosis journal August 2016
Munc18-2, but not Munc18-1 or Munc18-3, controls compound and single-vesicle–regulated exocytosis in mast cells journal March 2018
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Heterodimerization of UNC-13/RIM regulates synaptic vesicle release probability but not priming posted_content August 2018
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The Vesicle Priming Factor CAPS Functions as a Homodimer via C2 Domain Interactions to Promote Regulated Vesicle Exocytosis. text January 2016
HID-1 is required for homotypic fusion of immature secretory granules during maturation journal October 2016
Munc18-1 catalyzes neuronal SNARE assembly by templating SNARE association journal December 2018

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