Functions of SNAREs in intracellular membrane fusion and lipid bilayer mixing.

Intracellular membrane fusion occurs with exquisite coordination and specificity. Each fusion event requires three basic components: Rab-GTPases organize the fusion site; SNARE proteins act during fusion; and N-ethylmaleimide-sensitive factor (NSF) plus its cofactor alpha-SNAP are required for recycling or activation of the fusion machinery. Whereas Rab-GTPases seem to mediate the initial membrane contact, SNAREs appear to lie at the center of the fusion process. It is known that formation of complexes between SNAREs from apposed membranes is a prerequisite for lipid bilayer mixing; however, the biophysics and many details of SNARE function are still vague. Nevertheless, recent observations are shedding light on the role of SNAREs in membrane fusion. Structural studies are revealing the mechanisms by which SNARES form complexes and interact with other proteins. Furthermore, it is now apparent that the SNARE transmembrane segment not only anchors the protein but engages in SNARE-SNARE interactions and plays an active role in fusion. Recent work indicates that the fusion process itself may comprise two stages and proceed via a hemifusion intermediate.