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Munc18 reprograms the intrinsic neuronal SNARE complex assembly pathway
Biorxiv : the Preprint Server for Biology
|August 1, 2026
Summary
The order of SNARE protein assembly is crucial for synaptic vesicle exocytosis. Munc18 acts as a molecular chaperone, promoting the simultaneous assembly of SNARE proteins into functional fusion machines.
Area of Science:
- Molecular Biology
- Cell Biology
- Neuroscience
Background:
- SNARE proteins (syntaxin/SNAP-25B and synaptobrevin) form four-helix bundles essential for synaptic vesicle exocytosis.
- The precise sequence of SNARE motif interactions during assembly is not fully understood.
Purpose of the Study:
- To elucidate the sequential assembly mechanism of SNARE motifs.
- To investigate the regulatory roles of Munc18 and Munc13-1 in SNARE complex formation.
Main Methods:
- Fluorescence anisotropy was used for real-time order-of-addition experiments.
- Förster resonance energy transfer (FRET) based C-SCORE assay was developed to monitor SNAP-25B motif assembly.
- In vitro lipid mixing assays with full-length SNAREs were performed.
Main Results:
- The assembly order of SNARE motifs influences the formation of functional complexes.
- Munc18 promotes a concerted assembly mechanism, requiring all SNARE motifs simultaneously.
- Munc13-1 had no significant effect on SNARE assembly in this context.
- Munc18 may activate syntaxin by disaggregation.
Conclusions:
- Munc18 functions as a molecular chaperone, orchestrating the concurrent assembly of SNARE proteins.
- This chaperone activity is critical for the formation of functional SNARE complexes driving membrane fusion.
- The findings provide new insights into the regulation of synaptic exocytosis.
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