Fig. 1 | Nature Communications

Fig. 1

From: Munc18-1 is crucial to overcome the inhibition of synaptic vesicle fusion by αSNAP

Fig. 1

Model of how αSNAP inhibition ensures that synaptic vesicle fusion requires Munc18-1 and Munc13-1. The model postulates that syntaxin-1 can exist in different states on the pre-synaptic plasma membrane, including a state where syntaxin-1 forms a closed conformation that binds to Munc18-1 (state 0), various states where syntaxin-1 forms heterodimers with SNAP-25 (state 1, shown with a 2:1 stoichiometry) and a tetrameric state (state 2). Trans-SNARE complexes can be potentially formed by the SNAREs alone (state 3), or through the Munc18-1-Munc13-1-dependent pathway that starts at state 0, leading to state 4. αSNAP can inhibit synaptic vesicle fusion by binding to the syntaxin-1 tetramers, hindering Munc18-1 binding, by binding to syntaxin-1-SNAP-25 heterodimers, precluding SNARE complex assembly, and by binding to trans-SNARE complexes formed by SNAREs alone, preventing membrane fusion. The mechanism underlying the latter inhibition is unclear, but we speculate that binding of distinct αSNAP molecules to the SNAREs and to the apposed membranes hinders C-terminal SNARE complex zippering. In states 1–3, only two αSNAP molecules are shown for simplicity, but up to four molecules are expected to be able to bind to each SNARE four-helix bundle53. αSNAP cannot inhibit fusion through the pathway that starts with Munc18-1 bound to closed syntaxin-1 because this interaction impedes αSNAP binding and access of αSNAP to trans-SNARE complexes is obstructed by Munc18-1 and/or Munc13-1. Synaptotagmin-1 and complexin, not shown for simplicity, may also contribute to prevent αSNAP binding to trans-SNARE complexes. This obstruction also prevents disassembly of the trans-SNARE complexes by NSF-αSNAP36 (see Discussion)

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