Munc18-1 catalyzes neuronal SNARE assembly by templating SNARE association
Copyright policy )Munc18-1 catalyzes neuronal SNARE assembly by templating SNARE association
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.
- University of California System United States
- University of California, San Francisco United States
- School of Medicine Yale University United States
- Princeton University United States
- Department of Molecular Biology and Biochemistry University of California United States
SNARE proteins, Synaptosomal-Associated Protein 25, QH301-705.5, Vesicle-Associated Membrane Protein 2, Science, membrane fusion, Syntaxin 1, Membrane Fusion, Exocytosis, Munc18 Proteins, Animals, Humans, Amino Acid Sequence, Biology (General), Neurons, Sequence Homology, Amino Acid, optical tweezers, Q, R, Cell Biology, SNARE assembly, Rats, Sec1/Munc18 (SM) proteins, Mutation, Medicine, SNARE Proteins, template complex, Protein Binding
SNARE proteins, Synaptosomal-Associated Protein 25, QH301-705.5, Vesicle-Associated Membrane Protein 2, Science, membrane fusion, Syntaxin 1, Membrane Fusion, Exocytosis, Munc18 Proteins, Animals, Humans, Amino Acid Sequence, Biology (General), Neurons, Sequence Homology, Amino Acid, optical tweezers, Q, R, Cell Biology, SNARE assembly, Rats, Sec1/Munc18 (SM) proteins, Mutation, Medicine, SNARE Proteins, template complex, Protein Binding
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