Membrane fusion as a team effort

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Abstract
Since the discovery that tetanus and botulinum toxins inhibit synaptic vesicle fusion by cleaving three proteins (synaptobrevin/VAMP, SNAP-25, and syntaxin/HPC) at the synapse, it has been known that these proteins, and, by extension, their many homologs [subsequently referred to as SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors)] are essential for fusion (1–5). The discovery that these three proteins bind to each other (6), and do so in a parallel fashion that forces the membranes in which they reside into close proximity (7, 8), prompted a facile model of fusion: namely, that SNAREs generally form trans complexes that link the two membranes destined to fuse with each other and that the full assembly of the SNARE complexes then forces the membranes into such a close proximity that their phospholipid surfaces disintegrate and reanneal to form a bilayer in which the SNAREs are now in cis (reviewed in ref. 9). Initial experiments using liposome containing reconstituted SNARE proteins supported this model and led to the hypothesis that SNAREs by themselves are sufficient to account for the membrane fusion process, i.e., constitute a minimal fusion machinery (10). However, two lines of evidence raised doubts about this hypothesis. First, members of two other protein families, the SM proteins (Sec1/Munc18-like proteins) and the Rab proteins, were found in many in vivo systems to be required for fusion (reviewed in ref. 11). At the synapse, for example, deleting the SM protein Munc18–1 …