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

TitleMunc18-1 catalyzes neuronal SNARE assembly by templating SNARE association.
Publication TypeJournal Article
Year of Publication2018
AuthorsJiao, J, He, M, Port, SA, Baker, RW, Xu, Y, Qu, H, Xiong, Y, Wang, Y, Jin, H, Eisemann, TJ, Hughson, FM, Zhang, Y
JournalElife
Volume7
Date Published2018 12 12
ISSN2050-084X
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.

DOI10.7554/eLife.41771
Alternate JournalElife
PubMed ID30540253
PubMed Central IDPMC6320071
Grant ListT32GM007223 / 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