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

Xiaoyu Yang; Shen Wang; Yi Sheng; Mingshu Zhang; Wenjuan Zou; Lijie Wu; Lijun Kang; Jose Rizo-Rey; Rongguang Zhang; Tao Xu; Cong Ma

doi:10.1038/nsmb.3038

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

Xiaoyu Yang, Shen Wang, Yi Sheng, Mingshu Zhang, Wenjuan Zou, Lijie Wu, Lijun Kang, Jose Rizo-Rey, Rongguang Zhang, Tao Xu, Cong Ma

Research output: Contribution to journal › Article › peer-review

126 Scopus citations

Abstract

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. 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.

Original language	English (US)
Pages (from-to)	547-554
Number of pages	8
Journal	Nature Structural and Molecular Biology
Volume	22
Issue number	7
DOIs	https://doi.org/10.1038/nsmb.3038
State	Published - Jul 9 2015

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Structural Biology
Molecular Biology

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title = "Syntaxin opening by the MUN domain underlies the function of Munc13 in synaptic-vesicle priming",

abstract = "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. 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.",

author = "Xiaoyu Yang and Shen Wang and Yi Sheng and Mingshu Zhang and Wenjuan Zou and Lijie Wu and Lijun Kang and Jose Rizo-Rey and Rongguang Zhang and Tao Xu and Cong Ma",

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AU - Yang, Xiaoyu

AU - Wang, Shen

AU - Sheng, Yi

AU - Zhang, Mingshu

AU - Zou, Wenjuan

AU - Wu, Lijie

AU - Kang, Lijun

AU - Rizo-Rey, Jose

AU - Zhang, Rongguang

AU - Xu, Tao

AU - Ma, Cong

PY - 2015/7/9

Y1 - 2015/7/9

N2 - 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. 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.

AB - 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. 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.

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

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