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Science 323 (5913): 512-516

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

Alternative Zippering as an On-Off Switch for SNARE-Mediated Fusion

Claudio G. Giraudo,1*{dagger} Alejandro Garcia-Diaz,1{dagger} William S. Eng,1,2 Yuhang Chen,2 Wayne A. Hendrickson,2 Thomas J. Melia,1{dagger} James E. Rothman1*{dagger}

Abstract: Membrane fusion between vesicles and target membranes involves the zippering of a four-helix bundle generated by constituent helices derived from target– and vesicle–soluble N-ethylmaleimide–sensitive factor attachment protein receptors (SNAREs). In neurons, the protein complexin clamps otherwise spontaneous fusion by SNARE proteins, allowing neurotransmitters and other mediators to be secreted when and where they are needed as this clamp is released. The membrane-proximal accessory helix of complexin is necessary for clamping, but its mechanism of action is unknown. Here, we present experiments using a reconstituted fusion system that suggest a simple model in which the complexin accessory helix forms an alternative four-helix bundle with the target-SNARE near the membrane, preventing the vesicle-SNARE from completing its zippering.

1 Department of Physiology and Cellular Biophysics, Columbia University, College of Physicians and Surgeons, 1150 Saint Nicholas Avenue, Russ Berrie Building, Room 520, New York, NY 10032, USA.
2 Department of Biochemistry and Molecular Biophysics, Columbia University, and Howard Hughes Medical Institute, New York, NY 10032, USA.

{dagger} Present address: Department of Cell Biology, School of Medicine, Yale University, 333 Cedar Street, New Haven, CT 06520, USA.

* To whom correspondence should be addressed. E-mail: james.rothman{at} (J.E.R.); claudio.giraudo{at} (C.G.G.)

Synaptic vesicle recycling: steps and principles.
S. O. Rizzoli (2014)
EMBO J. 33, 788-822
   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 »
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 »
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 »
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 »
Evidence for a radial SNARE super-complex mediating neurotransmitter release at the Drosophila neuromuscular junction.
A. Megighian, M. Zordan, S. Pantano, M. Scorzeto, M. Rigoni, D. Zanini, O. Rossetto, and C. Montecucco (2013)
J. Cell Sci. 126, 3134-3140
   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 »
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 »
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 »
Adhesion energy can regulate vesicle fusion and stabilize partially fused states.
R. Long, C.-Y. Hui, A. Jagota, and M. Bykhovskaia (2012)
J R Soc Interface 9, 1555-1567
   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 »
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 »
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 »
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 »
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 »
Dynamic structure of lipid-bound synaptobrevin suggests a nucleation-propagation mechanism for trans-SNARE complex formation.
J. F. Ellena, B. Liang, M. Wiktor, A. Stein, D. S. Cafiso, R. Jahn, and L. K. Tamm (2009)
PNAS 106, 20306-20311
   Abstract »    Full Text »    PDF »
Discrimination between docking and fusion of liposomes reconstituted with neuronal SNARE-proteins using FCS.
A. Cypionka, A. Stein, J. M. Hernandez, H. Hippchen, R. Jahn, and P. J. Walla (2009)
PNAS 106, 18575-18580
   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 »
Complexin Controls the Force Transfer from SNARE Complexes to Membranes in Fusion.
A. Maximov, J. Tang, X. Yang, Z. P. Pang, and T. C. Sudhof (2009)
Science 323, 516-521
   Abstract »    Full Text »    PDF »

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