Fig. 9. Graphic representation of the working model of tomosyns attenuating SNARE assembly and synaptic depression.

a Munc18-1 sequesters syntaxin in a ‘closed’ conformation unable to associate with other SNAREs¹¹⁸. This closed dimer transits to an open conformation in which the SNARE motif is accessible, assisted by Munc13¹¹⁹. Syb2/VAMP2 binds to the open syntaxin complex to form the template complex in which the N-terminal regions of both SNARE motifs are aligned. Finally, tomosyns bind the VAMP2-containing template complex, preventing SNAP-25 binding and further SNARE assembly. b Schematic of the energy landscape for synaptic vesicle priming and fusion. Tomosyns bind the assembling template complex to produce a higher fusion barrier SNARE complex state lacking SNAP-25. As a result, a smaller fraction of the vesicle pool will be released upon stimulation, which reduces synaptic strength and limits synaptic depression.