Testing the SNARE/SM protein model of membrane fusion

Abstract

In eukaryotic cells, the budding and fusion of membranes mediates diverse but essential processes, ranging from cell division to organelle biogenesis to neurotransmitter secretion. All intracellular membrane fusion except for mitochondrial fusion is driven by SNARE and SM (Sec1/Munc18-like) proteins (1–3). Membrane fusion has been particularly intensely studied for neurotransmitter secretion. In neurotransmitter secretion, fusion is mediated by the plasma membrane SNARE proteins syntaxin and synaptosomal-associated protein 25 (SNAP-25), the vesicle SNARE protein synaptobrevin/vesicle-associated membrane protein (VAMP), and the SM protein Munc18-1 (Fig. 1 A and B). Mechanistically, SNARE proteins are thought to fuel fusion by forming a transcomplex between the vesicle and target membranes; in this complex, progressive zippering of a four-helical bundle formed by the SNARE motifs of SNARE proteins forces the fusing phospholipid membranes into close proximity, thereby destabilizing their surfaces (1–3). SM proteins are essential coagonists of SNARE proteins in fusion in that all intracellular SNARE-dependent fusion reactions require an SM protein.