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 323 (5913): 516-521

Copyright © 2009 by the American Association for the Advancement of Science

Complexin Controls the Force Transfer from SNARE Complexes to Membranes in Fusion

Anton Maximov,1* Jiong Tang,1{dagger} Xiaofei Yang,1,2 Zhiping P. Pang,1,2 Thomas C. Südhof1,2,3,4,5{ddagger}

Abstract: Trans–SNAP receptor (SNARE, where SNAP is defined as soluble NSF attachment protein, and NSF is defined as N-ethylmaleimide–sensitive factor) complexes catalyze synaptic vesicle fusion and bind complexin, but the function of complexin binding to SNARE complexes remains unclear. Here we show that in neuronal synapses, complexin simultaneously suppressed spontaneous fusion and activated fast calcium ion–evoked fusion. The dual function of complexin required SNARE binding and also involved distinct amino-terminal sequences of complexin that localize to the point where trans-SNARE complexes insert into the fusing membranes, suggesting that complexin controls the force that trans-SNARE complexes apply onto the fusing membranes. Consistent with this hypothesis, a mutation in the membrane insertion sequence of the v-SNARE synaptobrevin/vesicle-associated membrane protein (VAMP) phenocopied the complexin loss-of-function state without impairing complexin binding to SNARE complexes. Thus, complexin probably activates and clamps the force transfer from assembled trans-SNARE complexes onto fusing membranes.

1 Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
2 Department of Cellular and Molecular Physiology, Stanford University, 1050 Arastradero Road, Palo Alto, CA 94304–5543, USA.
3 Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas TX 75390, USA.
4 Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
5 Howard Hughes Medical Institute, Stanford University, Palo Alto, CA 94304–5543, USA.

* Present address: Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.

{dagger} Present address: Stanford University, Stanford, CA 94305, USA.

{ddagger} To whom correspondence should be addressed. E-mail: tcs1{at}

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 »
Complexin synchronizes primed vesicle exocytosis and regulates fusion pore dynamics.
M. Dhara, A. Yarzagaray, Y. Schwarz, S. Dutta, C. Grabner, P. K. Moghadam, A. Bost, C. Schirra, J. Rettig, K. Reim, et al. (2014)
J. Cell Biol. 204, 1123-1140
   Abstract »    Full Text »    PDF »
NAADP and the two-pore channel protein 1 participate in the acrosome reaction in mammalian spermatozoa.
L. Arndt, J. Castonguay, E. Arlt, D. Meyer, S. Hassan, H. Borth, S. Zierler, G. Wennemuth, A. Breit, M. Biel, et al. (2014)
Mol. Biol. Cell 25, 948-964
   Abstract »    Full Text »    PDF »
SNARE and regulatory proteins induce local membrane protrusions to prime docked vesicles for fast calcium-triggered fusion.
T. A. M. Bharat, J. Malsam, W. J. H. Hagen, A. Scheutzow, T. H. Sollner, and J. A. G. Briggs (2014)
EMBO Rep. 15, 308-314
   Abstract »    Full Text »    PDF »
Cognitive Enhancing Treatment with a PPAR{gamma} Agonist Normalizes Dentate Granule Cell Presynaptic Function in Tg2576 APP Mice.
M. N. Nenov, F. Laezza, S. J. Haidacher, Y. Zhao, R. G. Sadygov, J. M. Starkey, H. Spratt, B. A. Luxon, K. T. Dineley, and L. Denner (2014)
J. Neurosci. 34, 1028-1036
   Abstract »    Full Text »    PDF »
Deconstructing complexin function in activating and clamping Ca2+-triggered exocytosis by comparing knockout and knockdown phenotypes.
X. Yang, P. Cao, and T. C. Sudhof (2013)
PNAS 110, 20777-20782
   Abstract »    Full Text »    PDF »
Point Mutation in Syntaxin-1A Causes Abnormal Vesicle Recycling, Behaviors, and Short Term Plasticity.
Y. Watanabe, N. Katayama, K. Takeuchi, T. Togano, R. Itoh, M. Sato, M. Yamazaki, M. Abe, T. Sato, K. Oda, et al. (2013)
J. Biol. Chem. 288, 34906-34919
   Abstract »    Full Text »    PDF »
Position of UNC-13 in the active zone regulates synaptic vesicle release probability and release kinetics.
K. Zhou, T. M. Stawicki, A. Goncharov, and Y. Jin (2013)
eLife Sci 2, e01180
   Abstract »    Full Text »    PDF »
Synaptotagmin Interaction with SNAP-25 Governs Vesicle Docking, Priming, and Fusion Triggering.
R. Mohrmann, H. de Wit, E. Connell, P. S. Pinheiro, C. Leese, D. Bruns, B. Davletov, M. Verhage, and J. B. Sorensen (2013)
J. Neurosci. 33, 14417-14430
   Abstract »    Full Text »    PDF »
Complexin facilitates exocytosis and synchronizes vesicle release in two secretory model systems.
M.-Y. Lin, J. G. Rohan, H. Cai, K. Reim, C.-P. Ko, and R. H. Chow (2013)
J. Physiol. 591, 2463-2473
   Abstract »    Full Text »    PDF »
Stabilization of Spontaneous Neurotransmitter Release at Ribbon Synapses by Ribbon-Specific Subtypes of Complexin.
T. Vaithianathan, G. Zanazzi, D. Henry, W. Akmentin, and G. Matthews (2013)
J. Neurosci. 33, 8216-8226
   Abstract »    Full Text »    PDF »
Complexin Activates Exocytosis of Distinct Secretory Vesicles Controlled by Different Synaptotagmins.
P. Cao, X. Yang, and T. C. Sudhof (2013)
J. Neurosci. 33, 1714-1727
   Abstract »    Full Text »    PDF »
Fusion pore formation and expansion induced by Ca2+ and synaptotagmin 1.
Y. Lai, J. Diao, Y. Liu, Y. Ishitsuka, Z. Su, K. Schulten, T. Ha, and Y.-K. Shin (2013)
PNAS 110, 1333-1338
   Abstract »    Full Text »    PDF »
Complexin Controls Spontaneous and Evoked Neurotransmitter Release by Regulating the Timing and Properties of Synaptotagmin Activity.
R. A. Jorquera, S. Huntwork-Rodriguez, Y. Akbergenova, R. W. Cho, and J. T. Littleton (2012)
J. Neurosci. 32, 18234-18245
   Abstract »    Full Text »    PDF »
Membrane-Proximal Tryptophans of Synaptobrevin II Stabilize Priming of Secretory Vesicles.
M. Borisovska, Y. N. Schwarz, M. Dhara, A. Yarzagaray, S. Hugo, D. Narzi, S. W. I. Siu, J. Kesavan, R. Mohrmann, R. A. Bockmann, et al. (2012)
J. Neurosci. 32, 15983-15997
   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 »
Distinct Initial SNARE Configurations Underlying the Diversity of Exocytosis.
H. Kasai, N. Takahashi, and H. Tokumaru (2012)
Physiol Rev 92, 1915-1964
   Abstract »    Full Text »    PDF »
Complexin arrests a pool of docked vesicles for fast Ca2+-dependent release.
J. Malsam, D. Parisotto, T. A. M. Bharat, A. Scheutzow, J. M. Krause, J. A. G. Briggs, and T. H. Sollner (2012)
EMBO J. 31, 3270-3281
   Abstract »    Full Text »    PDF »
C-Terminal Complexin Sequence Is Selectively Required for Clamping and Priming But Not for Ca2+ Triggering of Synaptic Exocytosis.
Y. J. Kaeser-Woo, X. Yang, and T. C. Sudhof (2012)
J. Neurosci. 32, 2877-2885
   Abstract »    Full Text »    PDF »
Synaptic proteins promote calcium-triggered fast transition from point contact to full fusion.
J. Diao, P. Grob, D. J. Cipriano, M. Kyoung, Y. Zhang, S. Shah, A. Nguyen, M. Padolina, A. Srivastava, M. Vrljic, et al. (2012)
eLife Sci 1, e00109
   Abstract »    Full Text »    PDF »
Calcium Control of Neurotransmitter Release.
T. C. Sudhof (2012)
Cold Spring Harb Perspect Biol 4, a011353
   Abstract »    Full Text »    PDF »
A Signaling Mechanism Coupling Netrin-1/Deleted in Colorectal Cancer Chemoattraction to SNARE-Mediated Exocytosis in Axonal Growth Cones.
T. Cotrufo, F. Perez-Branguli, A. Muhaisen, O. Ros, R. Andres, T. Baeriswyl, G. Fuschini, T. Tarrago, M. Pascual, J. Urena, et al. (2011)
J. Neurosci. 31, 14463-14480
   Abstract »    Full Text »    PDF »
Neuroligins/LRRTMs prevent activity- and Ca2+/calmodulin-dependent synapse elimination in cultured neurons.
J. Ko, G. J. Soler-Llavina, M. V. Fuccillo, R. C. Malenka, and T. C. Sudhof (2011)
J. Cell Biol. 194, 323-334
   Abstract »    Full Text »    PDF »
An autism-associated point mutation in the neuroligin cytoplasmic tail selectively impairs AMPA receptor-mediated synaptic transmission in hippocampus.
M. R. Etherton, K. Tabuchi, M. Sharma, J. Ko, and T. C. Sudhof (2011)
EMBO J. 30, 2908-2919
   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 »
Preparation of the Cortical Reaction: Maturation-Dependent Migration of SNARE Proteins, Clathrin, and Complexin to the Porcine Oocyte's Surface Blocks Membrane Traffic until Fertilization.
P.-S. Tsai, T. van Haeften, and B. M. Gadella (2011)
Biol Reprod 84, 327-335
   Abstract »    Full Text »    PDF »
Dissection of SNARE-driven membrane fusion and neuroexocytosis by wedging small hydrophobic molecules into the SNARE zipper.
Y. Yang, J. Y. Shin, J.-M. Oh, C. H. Jung, Y. Hwang, S. Kim, J.-S. Kim, K.-J. Yoon, J.-Y. Ryu, J. Shin, et al. (2010)
PNAS 107, 22145-22150
   Abstract »    Full Text »    PDF »
Complexin 2 Modulates Vesicle-associated Membrane Protein (VAMP) 2-regulated Zymogen Granule Exocytosis in Pancreatic Acini.
M. A. Falkowski, D. D. H. Thomas, and G. E. Groblewski (2010)
J. Biol. Chem. 285, 35558-35566
   Abstract »    Full Text »    PDF »
Role of the synaptobrevin C terminus in fusion pore formation.
A. N. Ngatchou, K. Kisler, Q. Fang, A. M. Walter, Y. Zhao, D. Bruns, J. B. Sorensen, and M. Lindau (2010)
PNAS 107, 18463-18468
   Abstract »    Full Text »    PDF »
Noradrenaline inhibits exocytosis via the G protein {beta} subunit and refilling of the readily releasable granule pool via the i1/2 subunit.
Y. Zhao, Q. Fang, S. G. Straub, M. Lindau, and G. W. G. Sharp (2010)
J. Physiol. 588, 3485-3498
   Abstract »    Full Text »    PDF »
Opposing functions of two sub-domains of the SNARE-complex in neurotransmission.
J. P. Weber, K. Reim, and J. B. Sorensen (2010)
EMBO J. 29, 2477-2490
   Abstract »    Full Text »    PDF »
Calcium-dependent Regulation of SNARE-mediated Membrane Fusion by Calmodulin.
J. Di Giovanni, C. Iborra, Y. Maulet, C. Leveque, O. El Far, and M. Seagar (2010)
J. Biol. Chem. 285, 23665-23675
   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 »
Calmodulin Controls Synaptic Strength via Presynaptic Activation of Calmodulin Kinase II.
Z. P. Pang, P. Cao, W. Xu, and T. C. Sudhof (2010)
J. Neurosci. 30, 4132-4142
   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 »
The Making of Synaptic Ribbons: How They Are Built and What They Do.
F. Schmitz (2009)
Neuroscientist 15, 611-624
   Abstract »    PDF »
Minimal membrane docking requirements revealed by reconstitution of Rab GTPase-dependent membrane fusion from purified components.
C. Stroupe, C. M. Hickey, J. Mima, A. S. Burfeind, and W. Wickner (2009)
PNAS 106, 17626-17633
   Abstract »    Full Text »    PDF »
Complexin-I Is Required for High-Fidelity Transmission at the Endbulb of Held Auditory Synapse.
N. Strenzke, S. Chanda, C. Kopp-Scheinpflug, D. Khimich, K. Reim, A. V. Bulankina, A. Neef, F. Wolf, N. Brose, M. A. Xu-Friedman, et al. (2009)
J. Neurosci. 29, 7991-8004
   Abstract »    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 »
Alternative Zippering as an On-Off Switch for SNARE-Mediated Fusion.
C. G. Giraudo, A. Garcia-Diaz, W. S. Eng, Y. Chen, W. A. Hendrickson, T. J. Melia, and J. E. Rothman (2009)
Science 323, 512-516
   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