Title | Munc18-1 catalyzes neuronal SNARE assembly by templating SNARE association. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Jiao, J, He, M, Port, SA, Baker, RW, Xu, Y, Qu, H, Xiong, Y, Wang, Y, Jin, H, Eisemann, TJ, Hughson, FM, Zhang, Y |
Journal | Elife |
Volume | 7 |
Date Published | 2018 Dec 12 |
ISSN | 2050-084X |
Keywords | Amino Acid Sequence, Animals, Exocytosis, Humans, Membrane Fusion, Munc18 Proteins, Mutation, Neurons, Protein Binding, Rats, Sequence Homology, Amino Acid, SNARE Proteins, Synaptosomal-Associated Protein 25, Syntaxin 1, Vesicle-Associated Membrane Protein 2 |
Abstract | <p>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.</p> |
DOI | 10.7554/eLife.41771 |
Alternate Journal | Elife |
PubMed ID | 30540253 |
PubMed Central ID | PMC6320071 |
Grant List | T32GM007223 / GM / NIGMS NIH HHS / United States R01 GM120193 / GM / NIGMS NIH HHS / United States T32 GM007223 / GM / NIGMS NIH HHS / United States R01GM093341 / GM / NIGMS NIH HHS / United States R01GM071574 / GM / NIGMS NIH HHS / United States R01 GM093341 / GM / NIGMS NIH HHS / United States R01 GM071574 / GM / NIGMS NIH HHS / United States R01GM120193 / GM / NIGMS NIH HHS / United States |