Munc18-1 and soluble NSF attachment protein receptors (SNAREs) are critical for synaptic vesicle fusion. Munc18-1 binds to the SNARE syntaxin-1 folded into a closed conformation and to SNARE complexes containing open syntaxin-1. Understanding which steps in fusion depend on the latter interaction and whether Munc18-1 competes with other factors such as complexins for SNARE complex binding is critical to elucidate the mechanisms involved. In this study, we show that lentiviral expression of Munc18-1 rescues abrogation of release in Munc18-1 knockout mice. We describe point mutations in Munc18-1 that preserve tight binding to closed syntaxin-1 but markedly disrupt Munc18-1 binding to SNARE complexes containing open syntaxin-1. Lentiviral rescue experiments reveal that such disruption selectively impairs synaptic vesicle priming but not Ca 2+ -triggered fusion of primed vesicles. We also find that Munc18-1 and complexin-1 bind simultaneously to SNARE complexes. These results suggest that Munc18-1 binding to SNARE complexes mediates synaptic vesicle priming and that the resulting primed state involves a Munc18-1–SNARE–complexin macromolecular assembly that is poised for Ca 2+ triggering of fusion. Footnotes Abbreviations used in this paper: DIV, day in vitro; ITC, isothermal titration calorimetry; KO, knockout; NMR, nuclear magnetic resonance; RRP, readily releasable pool; SM, Sec1/Munc18; SMR, strongest methyl resonance; WT, wild type. Submitted: 4 December 2008 Accepted: 4 February 2009
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Munc18-1 binding to the neuronal SNARE complex controls synaptic vesicle priming
Deák, Ferenc; Xu, Yi; Chang, Wen-Pin; Dulubova, Irina; Khvotchev, Mikhail; Liu, Xinran; Südhof, Thomas C.; Rizo, Josep
Follow The Journal of Cell Biology
, Volume 184 (5): 751
Rockefeller University Press – Mar 9, 2009
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