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.
Gerber
Stefan H
SH
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390-9111, USA.
Rah
Jong-Cheol
JC
Min
Sang-Won
SW
Liu
Xinran
X
de Wit
Heidi
H
Dulubova
Irina
I
Meyer
Alexander C
AC
Rizo
Josep
J
Arancillo
Marife
M
Hammer
Robert E
RE
Verhage
Matthijs
M
Rosenmund
Christian
C
Südhof
Thomas C
TC
D000818:Animals; D002118:Calcium / Q000378:metabolism; D004827:Epilepsy / Q000209:etiology; D019706:Excitatory Postsynaptic Potentials; D008561:Membrane Fusion; D051379:Mice; D018345:Mice, Knockout; D051938:Munc18 Proteins / Q000378:metabolism; D009154:Mutation; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D050600:SNARE Proteins / Q000378:metabolism; D013395:Sucrose / Q000378:metabolism; D013569:Synapses / Q000502:physiology; D013572:Synaptic Vesicles / Q000502:physiology* / Q000648:ultrastructure; D050827:Syntaxin 1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D051938:Munc18 Proteins; D050600:SNARE Proteins; D050827:Syntaxin 1; D013395:Sucrose; D002118:Calcium