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Science 321 (5895): 1507-1510

Copyright © 2008 by the American Association for the Advancement of Science

Conformational Switch of Syntaxin-1 Controls Synaptic Vesicle Fusion

Stefan H. Gerber,1*{dagger} Jong-Cheol Rah,2,3*{ddagger} Sang-Won Min,1*§ Xinran Liu,1,4 Heidi de Wit,5 Irina Dulubova,6 Alexander C. Meyer,3 Josep Rizo,6,7 Marife Arancillo,2 Robert E. Hammer,6,7 Matthijs Verhage,5 Christian Rosenmund,2,3# Thomas C. Südhof1,4,8#

Abstract: 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.

{dagger} Present address: Abteilung Innere Medizin III, Universität Heidelberg, 69120 Heidelberg, Germany.

{ddagger} 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.

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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