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ReportsConformational 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-1BOpen 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-1BOpen 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.
1 Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390–9111, USA.
2 Department of Molecular and Human Genetics and Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA. 3 Department of Membrane Biophysics, Max-Planck-Institute for Biophysical Chemistry, 37077 Göttingen, Germany. 4 Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390–9111, USA. 5 Department of Functional Genomics, Vrije Universiteit, 1081 Amsterdam, Netherlands. 6 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390–9111, USA. 7 Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390–9111, USA. 8 Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390–9111, USA. * These authors contributed equally to this work.
¶ Present address: Department of Molecular and Cellular Physiology and Neuroscience Institute, Stanford University, Palo Alto, CA 94304–5543, USA. # To whom correspondence should be addressed. E-mail: rosenmun{at}bcm.tmc.edu (C.R.); tcs1{at}stanford.edu (T.C.S.)
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Present address: Abteilung Innere Medizin III, Universität Heidelberg, 69120 Heidelberg, Germany. 
Present address: Developmental Synaptic Plasticity Section, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892, USA. 
Present address: University of California, San Francisco, Mission Bay Campus, San Francisco, CA 94158, USA. Science. ISSN 0036-8075 (print), 1095-9203 (online)
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