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Conformational Switch of Syntaxin-1 Controls Synaptic Vesicle Fusion

Stefan H. Gerber, Jong-Cheol Rah, Sang-Won Min, Xinran Liu, Heidi de Wit, Irina Dulubova, Alexander C. Meyer, Josep Rizo, Marife Arancillo, Robert E. Hammer, Matthijs Verhage, Christian Rosenmund and Thomas C. Südhof
Science
New Series, Vol. 321, No. 5895 (Sep. 12, 2008), pp. 1507-1510
Stable URL: http://www.jstor.org/stable/20144808
Page Count: 4
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Conformational Switch of Syntaxin-1 Controls Synaptic Vesicle Fusion
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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-$1\text{B}^{\text{Open}}$ 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-$1\text{B}^{\text{Open}}$ 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.

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