Two gigs of Munc18 in membrane fusion

All membrane fusion in eukaryotic cells, except mitochondrial and homotypic endoplasmic reticulum fusion, is critically dependent upon evolutionarily conserved soluble N-ethylmaleimide–sensitive factor attachment protein receptors (SNAREs) and Sec1/Muc18 (SM) proteins (1, 2). Similar to the cases for SNARE proteins, all SM-null mutants, from yeast to rat, exhibit a significant to complete loss of specific membrane fusion events (3, 4), suggesting the possibility of a conserved mechanism for the SM protein family. The SNARE proteins, as a central fusogen, have been well documented (5). In stark contrast, the function of SM proteins has been elusive, despite intense investigations. In PNAS, Yu et al. (6) present unique and exciting results that provide insights into the mechanism by which SM–SNARE interactions play out in driving intracellular membrane fusion. To allow vesicle fusion to happen, cognate SNARE partners from two membranes associate with each other to form a parallel four-helix bundle that brings about the apposition of two membranes, facilitating fusion (7, 8). Among the SM family, neuronal Munc18-1 was the first member structurally characterized in context with SNAREs in high resolution (9). From the structure, it is evident that arch-shaped Munc18-1 binds the closed form of helical syntaxin 1a (Fig. 1A), one of the two target membrane (t-) SNAREs. Such capping of syntaxin 1a inhibits otherwise spontaneous binding to a second t-SNARE protein synaptosomal-associated protein 25 (SNAP-25) and subsequent engagement with vesicle (v-) SNARE vesicle-associated membrane protein 2 (VAMP2). As such, the data appear to contradict the expected critically positive role of Munc18-1 in membrane fusion, creating more problems than solutions (2). Two modes of Munc18 binding to SNAREs. (A) Munc18 binds to the closed form of syntaxin. Syntaxin is composed of four structurally distinct regions: a membrane-spanning helix, an ∼70 residue-long SNARE …