Figure 7. Models illustrating the different geometric constraints of cis- and trans-SNARE complex disassembly.

(A,B) Models showing ribbon diagrams of the cryo-electron microscopy structure of the 20S complex (PDB accession code 3J96) (Zhao et al., 2015) assembled on a cis-SNARE complex on one membrane (A) or on a trans-SNARE complex between two membranes (B). Synaptobrevin is in red, syntaxin-1 in yellow, SNAP-25 in green, NSF in gray and the four molecules of αSNAP in cyan, orange, blue and pink. The positions of the αSNAP N-terminal hydrophobic loops (N-loops) are indicated. The orientation of the 20S complex in (A) was chosen to favor simultaneous interactions of the N-loops of the four αSNAP molecules with the membrane. In (B), the orientation of the 20S complex is arbitrary and is meant to illustrate the difficulty of simultaneous interactions of the N-loops from the four αSNAP molecules with membranes in the trans configuration. Note that, at the same time, the apposition of both membranes may enhance the affinity of Munc18-1, Munc13-1, synaptotagmin-1 and complexin-1 for SNARE complexes in the trans configuration due to simultaneous interactions with the membranes that are not possible or less favorable in the cis configuration, while the SNARE four-helix bundle is likely to be only partially assembled, which may weaken binding to αSNAP.