Munc18-1 catalyzes neuronal SNARE assembly by templating SNARE association

Junyi Jiao; Mengze He; Sarah A. Port; Richard W. Baker; Yonggang Xu; Hong Qu; Yujian Xiong; Yukun Wang; Huaizhou Jin; Travis J. Eisemann; Frederick M. Hughson; Yongli Zhang

doi:10.7554/eLife.41771

Munc18-1 catalyzes neuronal SNARE assembly by templating SNARE association

Junyi Jiao, Mengze He, Sarah A. Port, Richard W. Baker, Yonggang Xu, Hong Qu, Yujian Xiong, Yukun Wang, Huaizhou Jin, Travis J. Eisemann, Frederick M. Hughson, Yongli Zhang

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

98 Scopus citations

Abstract

Sec1/Munc18-family (SM) proteins are required for SNARE-mediated membrane fusion, but their mechanism(s) of action remain controversial. Using single-molecule force spectroscopy, we found that the SM protein Munc18-1 catalyzes step-wise zippering of three synaptic SNAREs (syntaxin, VAMP2, and SNAP-25) into a four-helix bundle. Catalysis requires formation of an intermediate template complex in which Munc18-1 juxtaposes the N-terminal regions of the SNARE motifs of syntaxin and VAMP2, while keeping their C-terminal regions separated. SNAP-25 binds the templated SNAREs to induce full SNARE zippering. Munc18-1 mutations modulate the stability of the template complex in a manner consistent with their effects on membrane fusion, indicating that chaperoned SNARE assembly is essential for exocytosis. Two other SM proteins, Munc18-3 and Vps33, similarly chaperone SNARE assembly via a template complex, suggesting that SM protein mechanism is conserved.

Original language	English (US)
Article number	e41771
Journal	eLife
Volume	7
DOIs	https://doi.org/10.7554/eLife.41771
State	Published - Dec 1 2018

All Science Journal Classification (ASJC) codes

General Neuroscience
General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology

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10.7554/eLife.41771

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title = "Munc18-1 catalyzes neuronal SNARE assembly by templating SNARE association",

abstract = "Sec1/Munc18-family (SM) proteins are required for SNARE-mediated membrane fusion, but their mechanism(s) of action remain controversial. Using single-molecule force spectroscopy, we found that the SM protein Munc18-1 catalyzes step-wise zippering of three synaptic SNAREs (syntaxin, VAMP2, and SNAP-25) into a four-helix bundle. Catalysis requires formation of an intermediate template complex in which Munc18-1 juxtaposes the N-terminal regions of the SNARE motifs of syntaxin and VAMP2, while keeping their C-terminal regions separated. SNAP-25 binds the templated SNAREs to induce full SNARE zippering. Munc18-1 mutations modulate the stability of the template complex in a manner consistent with their effects on membrane fusion, indicating that chaperoned SNARE assembly is essential for exocytosis. Two other SM proteins, Munc18-3 and Vps33, similarly chaperone SNARE assembly via a template complex, suggesting that SM protein mechanism is conserved.",

author = "Junyi Jiao and Mengze He and Port, {Sarah A.} and Baker, {Richard W.} and Yonggang Xu and Hong Qu and Yujian Xiong and Yukun Wang and Huaizhou Jin and Eisemann, {Travis J.} and Hughson, {Frederick M.} and Yongli Zhang",

note = "Publisher Copyright: {\textcopyright} Jiao et al.",

year = "2018",

month = dec,

day = "1",

doi = "10.7554/eLife.41771",

language = "English (US)",

volume = "7",

journal = "eLife",

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T1 - Munc18-1 catalyzes neuronal SNARE assembly by templating SNARE association

AU - Jiao, Junyi

AU - He, Mengze

AU - Port, Sarah A.

AU - Baker, Richard W.

AU - Xu, Yonggang

AU - Qu, Hong

AU - Xiong, Yujian

AU - Wang, Yukun

AU - Jin, Huaizhou

AU - Eisemann, Travis J.

AU - Hughson, Frederick M.

AU - Zhang, Yongli

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Sec1/Munc18-family (SM) proteins are required for SNARE-mediated membrane fusion, but their mechanism(s) of action remain controversial. Using single-molecule force spectroscopy, we found that the SM protein Munc18-1 catalyzes step-wise zippering of three synaptic SNAREs (syntaxin, VAMP2, and SNAP-25) into a four-helix bundle. Catalysis requires formation of an intermediate template complex in which Munc18-1 juxtaposes the N-terminal regions of the SNARE motifs of syntaxin and VAMP2, while keeping their C-terminal regions separated. SNAP-25 binds the templated SNAREs to induce full SNARE zippering. Munc18-1 mutations modulate the stability of the template complex in a manner consistent with their effects on membrane fusion, indicating that chaperoned SNARE assembly is essential for exocytosis. Two other SM proteins, Munc18-3 and Vps33, similarly chaperone SNARE assembly via a template complex, suggesting that SM protein mechanism is conserved.

AB - Sec1/Munc18-family (SM) proteins are required for SNARE-mediated membrane fusion, but their mechanism(s) of action remain controversial. Using single-molecule force spectroscopy, we found that the SM protein Munc18-1 catalyzes step-wise zippering of three synaptic SNAREs (syntaxin, VAMP2, and SNAP-25) into a four-helix bundle. Catalysis requires formation of an intermediate template complex in which Munc18-1 juxtaposes the N-terminal regions of the SNARE motifs of syntaxin and VAMP2, while keeping their C-terminal regions separated. SNAP-25 binds the templated SNAREs to induce full SNARE zippering. Munc18-1 mutations modulate the stability of the template complex in a manner consistent with their effects on membrane fusion, indicating that chaperoned SNARE assembly is essential for exocytosis. Two other SM proteins, Munc18-3 and Vps33, similarly chaperone SNARE assembly via a template complex, suggesting that SM protein mechanism is conserved.

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Munc18-1 catalyzes neuronal SNARE assembly by templating SNARE association

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