Autoinhibition of Munc18-1 modulates synaptobrevin binding and helps to enable Munc13-dependent regulation of membrane fusion

Elife. 2017 May 6:6:e24278. doi: 10.7554/eLife.24278.


Munc18-1 orchestrates SNARE complex assembly together with Munc13-1 to mediate neurotransmitter release. Munc18-1 binds to synaptobrevin, but the relevance of this interaction and its relation to Munc13 function are unclear. NMR experiments now show that Munc18-1 binds specifically and non-specifically to synaptobrevin. Specific binding is inhibited by a L348R mutation in Munc18-1 and enhanced by a D326K mutation designed to disrupt the 'furled conformation' of a Munc18-1 loop. Correspondingly, the activity of Munc18-1 in reconstitution assays that require Munc18-1 and Munc13-1 for membrane fusion is stimulated by the D326K mutation and inhibited by the L348R mutation. Moreover, the D326K mutation allows Munc13-1-independent fusion and leads to a gain-of-function in rescue experiments in Caenorhabditis elegans unc-18 nulls. Together with previous studies, our data support a model whereby Munc18-1 acts as a template for SNARE complex assembly, and autoinhibition of synaptobrevin binding contributes to enabling regulation of neurotransmitter release by Munc13-1.

Keywords: C. elegans; Munc13; Munc18-1; autoinhibition; biophysics; mouse; neuroscience; neurotransmitter release; protein NMR; structural biology.

MeSH terms

  • Animals
  • Calorimetry
  • Magnetic Resonance Spectroscopy
  • Membrane Fusion*
  • Munc18 Proteins / metabolism*
  • Nerve Tissue Proteins / metabolism*
  • R-SNARE Proteins / metabolism*
  • Rats
  • SNARE Proteins / metabolism*


  • Munc18 Proteins
  • Nerve Tissue Proteins
  • R-SNARE Proteins
  • SNARE Proteins
  • Stxbp1 protein, rat
  • Unc13a protein, rat