Synapses continually replenish their synaptic vesicle (SV) pools while suppressing spontaneous fusion events, thus maintaining a high dynamic range in response to physiological stimuli. The presynaptic protein complexin can both promote and inhibit fusion through interactions between its α-helical domain and the SNARE complex. In addition, complexin@s C-terminal half is required for the inhibition of spontaneous fusion in worm, fly, and mouse, although the molecular mechanism remains unexplained. We show here that complexin@s C-terminal domain binds lipids through a novel protein motif, permitting complexin to inhibit spontaneous exocytosis in vivo by targeting complexin to SVs. We propose that the SV pool serves as a platform to sequester and position complexin where it can intercept the rapidly assembling SNAREs and control the rate of spontaneous fusion.
Wragg, R. T., Snead, D., Dong, Y., Ramlall, T. F., Menon, I., Bai, J., … Dittman, J. S. (2013). Synaptic Vesicles Position Complexin to Block Spontaneous Fusion. Neuron, 77(2), 323–334. https://doi.org/10.1016/j.neuron.2012.11.005