Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

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} (C.R.); tcs1{at} (T.C.S.)

Ca2+-Calmodulin regulates SNARE assembly and spontaneous neurotransmitter release via v-ATPase subunit V0a1.
D. Wang, D. Epstein, O. Khalaf, S. Srinivasan, W. R. Williamson, A. Fayyazuddin, F. A. Quiocho, and P. R. Hiesinger (2014)
J. Cell Biol. 205, 21-31
   Abstract »    Full Text »    PDF »
An Extended Helical Conformation in Domain 3a of Munc18-1 Provides a Template for SNARE (Soluble N-Ethylmaleimide-sensitive Factor Attachment Protein Receptor) Complex Assembly.
D. Parisotto, M. Pfau, A. Scheutzow, K. Wild, M. P. Mayer, J. Malsam, I. Sinning, and T. H. Sollner (2014)
J. Biol. Chem. 289, 9639-9650
   Abstract »    Full Text »    PDF »
A Novel Mutation in STXBP1 Gene in a Child With Epileptic Encephalopathy and an Atypical Electroclinical Pattern.
R. Romaniello, C. Zucca, E. Tenderini, F. Arrigoni, F. Ragona, G. Zorzi, M. T. Bassi, and R. Borgatti (2014)
J Child Neurol 29, 249-253
   Abstract »    Full Text »    PDF »
Vps33b pathogenic mutations preferentially affect VIPAS39/SPE-39-positive endosomes.
K. Tornieri, S. A. Zlatic, A. P. Mullin, E. Werner, R. Harrison, S. W. L'Hernault, and V. Faundez (2013)
Hum. Mol. Genet. 22, 5215-5228
   Abstract »    Full Text »    PDF »
Prefusion structure of syntaxin-1A suggests pathway for folding into neuronal trans-SNARE complex fusion intermediate.
B. Liang, V. Kiessling, and L. K. Tamm (2013)
PNAS 110, 19384-19389
   Abstract »    Full Text »    PDF »
Deciphering Dead-End Docking of Large Dense Core Vesicles in Bovine Chromaffin Cells.
S. Hugo, E. Dembla, M. Halimani, U. Matti, J. Rettig, and U. Becherer (2013)
J. Neurosci. 33, 17123-17137
   Abstract »    Full Text »    PDF »
Titration of Syntaxin1 in Mammalian Synapses Reveals Multiple Roles in Vesicle Docking, Priming, and Release Probability.
M. Arancillo, S.-W. Min, S. Gerber, A. Munster-Wandowski, Y.-J. Wu, M. Herman, T. Trimbuch, J.-C. Rah, G. Ahnert-Hilger, D. Riedel, et al. (2013)
J. Neurosci. 33, 16698-16714
   Abstract »    Full Text »    PDF »
Comparative studies of Munc18c and Munc18-1 reveal conserved and divergent mechanisms of Sec1/Munc18 proteins.
H. Yu, S. S. Rathore, J. A. Lopez, E. M. Davis, D. E. James, J. L. Martin, and J. Shen (2013)
PNAS 110, E3271-E3280
   Abstract »    Full Text »    PDF »
Syntaxin1a variants lacking an N-peptide or bearing the LE mutation bind to Munc18a in a closed conformation.
K. N. Colbert, D. A. Hattendorf, T. M. Weiss, P. Burkhardt, D. Fasshauer, and W. I. Weis (2013)
PNAS 110, 12637-12642
   Abstract »    Full Text »    PDF »
Ultrahigh-resolution imaging reveals formation of neuronal SNARE/Munc18 complexes in situ.
A. Pertsinidis, K. Mukherjee, M. Sharma, Z. P. Pang, S. R. Park, Y. Zhang, A. T. Brunger, T. C. Sudhof, and S. Chu (2013)
PNAS 110, E2812-E2820
   Abstract »    Full Text »    PDF »
Munc18b Is a Major Mediator of Insulin Exocytosis in Rat Pancreatic {beta}-Cells.
P. P. L. Lam, M. Ohno, S. Dolai, Y. He, T. Qin, T. Liang, D. Zhu, Y. Kang, Y. Liu, M. Kauppi, et al. (2013)
Diabetes 62, 2416-2428
   Abstract »    Full Text »    PDF »
Domain 3a of Munc18-1 plays a crucial role at the priming stage of exocytosis.
G. A. Han, N.-R. Bin, S.-Y. A. Kang, L. Han, and S. Sugita (2013)
J. Cell Sci. 126, 2361-2371
   Abstract »    Full Text »    PDF »
Large {alpha}-synuclein oligomers inhibit neuronal SNARE-mediated vesicle docking.
B.-K. Choi, M.-G. Choi, J.-Y. Kim, Y. Yang, Y. Lai, D.-H. Kweon, N. K. Lee, and Y.-K. Shin (2013)
PNAS 110, 4087-4092
   Abstract »    Full Text »    PDF »
Munc18-1 Protein Molecules Move between Membrane Molecular Depots Distinct from Vesicle Docking Sites.
A. M. Smyth, L. Yang, K. J. Martin, C. Hamilton, W. Lu, M. A. Cousin, C. Rickman, and R. R. Duncan (2013)
J. Biol. Chem. 288, 5102-5113
   Abstract »    Full Text »    PDF »
Syntaxin-1 N-peptide and Habc-domain perform distinct essential functions in synaptic vesicle fusion.
P. Zhou, Z. P. Pang, X. Yang, Y. Zhang, C. Rosenmund, T. Bacaj, and T. C. Sudhof (2013)
EMBO J. 32, 159-171
   Abstract »    Full Text »    PDF »
G{beta}{gamma} Inhibits Exocytosis via Interaction with Critical Residues on Soluble N-Ethylmaleimide-Sensitive Factor Attachment Protein-25.
C. A. Wells, Z. Zurawski, K. M. Betke, Y. Y. Yim, K. Hyde, S. Rodriguez, S. Alford, and H. E. Hamm (2012)
Mol. Pharmacol. 82, 1136-1149
   Abstract »    Full Text »    PDF »
Ectopic Vesicular Glutamate Release at the Optic Nerve Head and Axon Loss in Mouse Experimental Glaucoma.
C. T. Fu and D. W. Sretavan (2012)
J. Neurosci. 32, 15859-15876
   Abstract »    Full Text »    PDF »
Enlightening molecular mechanisms through study of protein interactions.
J. Rizo, M. K. Rosen, and K. H. Gardner (2012)
J Mol Cell Biol 4, 270-283
   Abstract »    Full Text »    PDF »
All three components of the neuronal SNARE complex contribute to secretory vesicle docking.
Y. Wu, Y. Gu, M. K. Morphew, J. Yao, F. L. Yeh, M. Dong, and E. R. Chapman (2012)
J. Cell Biol. 198, 323-330
   Abstract »    Full Text »    PDF »
RIM genes differentially contribute to organizing presynaptic release sites.
P. S. Kaeser, L. Deng, M. Fan, and T. C. Sudhof (2012)
PNAS 109, 11830-11835
   Abstract »    Full Text »    PDF »
A Novel STXBP1 Mutation Causes Focal Seizures With Neonatal Onset.
M. Vatta, M. B. Tennison, A. S. Aylsworth, C. M. Turcott, M. P. Guerra, C. M. Eng, and Y. Yang (2012)
J Child Neurol 27, 811-814
   Abstract »    Full Text »    PDF »
GLUT4 exocytosis.
J. Stockli, D. J. Fazakerley, and D. E. James (2011)
J. Cell Sci. 124, 4147-4159
   Abstract »    Full Text »    PDF »
Synaptic Vesicle Exocytosis.
T. C. Sudhof and J. Rizo (2011)
Cold Spring Harb Perspect Biol 3, a005637
   Abstract »    Full Text »    PDF »
Syntaxin1A Lateral Diffusion Reveals Transient and Local SNARE Interactions.
C. Ribrault, J. Reingruber, M. Petkovic, T. Galli, N. E. Ziv, D. Holcman, and A. Triller (2011)
J. Neurosci. 31, 17590-17602
   Abstract »    Full Text »    PDF »
Dual roles of Munc18-1 rely on distinct binding modes of the central cavity with Stx1A and SNARE complex.
L. Shi, D. Kummel, J. Coleman, T. J. Melia, and C. G. Giraudo (2011)
Mol. Biol. Cell 22, 4150-4160
   Abstract »    Full Text »    PDF »
Activation of metabotropic GABA receptors increases the energy barrier for vesicle fusion.
B. R. Rost, P. Nicholson, G. Ahnert-Hilger, A. Rummel, C. Rosenmund, J. Breustedt, and D. Schmitz (2011)
J. Cell Sci. 124, 3066-3073
   Abstract »    Full Text »    PDF »
In vitro system capable of differentiating fast Ca2+-triggered content mixing from lipid exchange for mechanistic studies of neurotransmitter release.
M. Kyoung, A. Srivastava, Y. Zhang, J. Diao, M. Vrljic, P. Grob, E. Nogales, S. Chu, and A. T. Brunger (2011)
PNAS 108, E304-E313
   Abstract »    Full Text »    PDF »
Possible roles for Munc18-1 domain 3a and Syntaxin1 N-peptide and C-terminal anchor in SNARE complex formation.
S.-H. Hu, M. P. Christie, N. J. Saez, C. F. Latham, R. Jarrott, L. H. L. Lua, B. M. Collins, and J. L. Martin (2011)
PNAS 108, 1040-1045
   Abstract »    Full Text »    PDF »
Syntaxin N-terminal peptide motif is an initiation factor for the assembly of the SNARE-Sec1/Munc18 membrane fusion complex.
S. S. Rathore, E. G. Bend, H. Yu, M. Hammarlund, E. M. Jorgensen, and J. Shen (2010)
PNAS 107, 22399-22406
   Abstract »    Full Text »    PDF »
Testing the SNARE/SM protein model of membrane fusion.
T. Bacaj, Z. P. Pang, and T. C. Sudhof (2010)
PNAS 107, 22365-22366
   Full Text »    PDF »
Syntaxin clusters assemble reversibly at sites of secretory granules in live cells.
S. Barg, M. K. Knowles, X. Chen, M. Midorikawa, and W. Almers (2010)
PNAS 107, 20804-20809
   Abstract »    Full Text »    PDF »
Deficiency in RNA editing enzyme ADAR2 impairs regulated exocytosis.
L. Yang, L. Zhao, Z. Gan, Z. He, J. Xu, X. Gao, X. Wang, W. Han, L. Chen, T. Xu, et al. (2010)
FASEB J 24, 3720-3732
   Abstract »    Full Text »    PDF »
Two distinct secretory vesicle-priming steps in adrenal chromaffin cells.
Y. Liu, C. Schirra, L. Edelmann, U. Matti, J. Rhee, D. Hof, D. Bruns, N. Brose, H. Rieger, D. R. Stevens, et al. (2010)
J. Cell Biol. 190, 1067-1077
   Abstract »    Full Text »    PDF »
Rapid Activation of Dormant Presynaptic Terminals by Phorbol Esters.
C. Y. Chang, X. Jiang, K. L. Moulder, and S. Mennerick (2010)
J. Neurosci. 30, 10048-10060
   Abstract »    Full Text »    PDF »
SNARE bundle and syntaxin N-peptide constitute a minimal complement for Munc18-1 activation of membrane fusion.
J. Shen, S. S. Rathore, L. Khandan, and J. E. Rothman (2010)
J. Cell Biol. 190, 55-63
   Abstract »    Full Text »    PDF »
A Coiled Coil Trigger Site Is Essential for Rapid Binding of Synaptobrevin to the SNARE Acceptor Complex.
K. Wiederhold, T. H. Kloepper, A. M. Walter, A. Stein, N. Kienle, J. B. Sorensen, and D. Fasshauer (2010)
J. Biol. Chem. 285, 21549-21559
   Abstract »    Full Text »    PDF »
The Longin SNARE VAMP7/TI-VAMP Adopts a Closed Conformation.
S. Vivona, C. W. Liu, P. Strop, V. Rossi, F. Filippini, and A. T. Brunger (2010)
J. Biol. Chem. 285, 17965-17973
   Abstract »    Full Text »    PDF »
Piccolo and bassoon maintain synaptic vesicle clustering without directly participating in vesicle exocytosis.
K. Mukherjee, X. Yang, S. H. Gerber, H.-B. Kwon, A. Ho, P. E. Castillo, X. Liu, and T. C. Sudhof (2010)
PNAS 107, 6504-6509
   Abstract »    Full Text »    PDF »
Secretory granules in inositol 1,4,5-trisphosphate-dependent Ca2+ signaling in the cytoplasm of neuroendocrine cells.
S. H. Yoo (2010)
FASEB J 24, 653-664
   Abstract »    Full Text »    PDF »
Exocytosis mechanisms underlying insulin release and glucose uptake: conserved roles for Munc18c and syntaxin 4.
J. L. Jewell, E. Oh, and D. C. Thurmond (2010)
Am J Physiol Regulatory Integrative Comp Physiol 298, R517-R531
   Abstract »    Full Text »    PDF »
Synaptobrevin N-terminally bound to syntaxin-SNAP-25 defines the primed vesicle state in regulated exocytosis.
A. M. Walter, K. Wiederhold, D. Bruns, D. Fasshauer, and J. B. Sorensen (2010)
J. Cell Biol. 188, 401-413
   Abstract »    Full Text »    PDF »
Quantitative analysis of the native presynaptic cytomatrix by cryoelectron tomography.
R. Fernandez-Busnadiego, B. Zuber, U. E. Maurer, M. Cyrklaff, W. Baumeister, and V. Lucic (2010)
J. Cell Biol. 188, 145-156
   Abstract »    Full Text »    PDF »
Newcomer insulin secretory granules as a highly calcium-sensitive pool.
M. G. Pedersen and A. Sherman (2009)
PNAS 106, 7432-7436
   Abstract »    Full Text »    PDF »
Munc18-1 binding to the neuronal SNARE complex controls synaptic vesicle priming.
F. Deak, Y. Xu, W.-P. Chang, I. Dulubova, M. Khvotchev, X. Liu, T. C. Sudhof, and J. Rizo (2009)
J. Cell Biol. 184, 751-764
   Abstract »    Full Text »    PDF »
Highlights From The Literature.
Physiology 24, 4-7
   Full Text »    PDF »
Membrane Fusion: Grappling with SNARE and SM Proteins.
T. C. Sudhof and J. E. Rothman (2009)
Science 323, 474-477
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882