Conformational switch of syntaxin-1 controls synaptic vesicle fusion

During synaptic vesicle fusion, the soluble N- ethylmaleimide- sensitive factor- attachment protein receptor ( SNARE) protein syntaxin- 1 exhibits two conformations that both bind to Munc18- 1: a "closed" conformation outside the SNARE complex and an "open" conformation in the SNARE complex. Although SNARE complexes containing open syntaxin- 1 and Munc18- 1 are essential for exocytosis, the function of closed syntaxin- 1 is unknown. We generated knockin/knockout mice that expressed only open syntaxin- 1B. Syntaxin- 1B(Open) mice were viable but succumbed to generalized seizures at 2 to 3 months of age. Binding of Munc18- 1 to syntaxin- 1 was impaired in syntaxin- 1B(Open) synapses, and the size of the readily releasable vesicle pool was decreased; however, the rate of synaptic vesicle fusion was dramatically enhanced. Thus, the closed conformation of syntaxin- 1 gates the initiation of the synaptic vesicle fusion reaction, which is then mediated by SNARE- complex/ Munc18- 1 assemblies.