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, Jose Rizo-Rey, Marife Arancillo, Robert E Hammer, Matthijs Verhage, Christian Rosenmund, Thomas C. Südhof

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194 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1507-1510
Number of pages4
JournalScience
Volume321
Issue number5895
DOIs
StatePublished - Sep 12 2008

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    Gerber, S. H., Rah, J. C., Min, S. W., Liu, X., De Wit, H., Dulubova, I., Meyer, A. C., Rizo-Rey, J., Arancillo, M., Hammer, R. E., Verhage, M., Rosenmund, C., & Südhof, T. C. (2008). Conformational switch of syntaxin-1 controls synaptic vesicle fusion. Science, 321(5895), 1507-1510. https://doi.org/10.1126/science.1163174