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Originally published in Science Express on 22 June 2006
Science 4 August 2006:
Vol. 313. no. 5787, pp. 676 - 680
DOI: 10.1126/science.1129450
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Reports

A Clamping Mechanism Involved in SNARE-Dependent Exocytosis

Claudio G. Giraudo, William S. Eng, Thomas J. Melia, James E. Rothman*

During neurotransmitter release at the synapse, influx of calcium ions stimulates the release of neurotransmitter. However, the mechanism by which synaptic vesicle fusion is coupled to calcium has been unclear, despite the identification of both the core fusion machinery [soluble N-ethylmaleimide–sensitive factor attachment protein receptor (SNARE)] and the principal calcium sensor (synaptotagmin). Here, we describe what may represent a basic principle of the coupling mechanism: a reversible clamping protein (complexin) that can freeze the SNAREpin, an assembled fusion-competent intermediate en route to fusion. When calcium binds to the calcium sensor synaptotagmin, the clamp would then be released. SNARE proteins, and key regulators like synaptotagmin and complexin, can be ectopically expressed on the cell surface. Cells expressing such "flipped" synaptic SNAREs fuse constitutively, but when we coexpressed complexin, fusion was blocked. Adding back calcium triggered fusion from this intermediate in the presence of synaptotagmin.

Department of Physiology and Cellular Biophysics, Columbia University, New York, NY 10032, USA.

* To whom correspondence should be addressed. E-mail: jr2269{at}columbia.edu

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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Distinct Domains of Complexins Bind SNARE Complexes and Clamp Fusion in Vitro.
C. G. Giraudo, A. Garcia-Diaz, W. S. Eng, A. Yamamoto, T. J. Melia, and J. E. Rothman (2008)
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Complexins facilitate neurotransmitter release at excitatory and inhibitory synapses in mammalian central nervous system.
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Impaired insulin secretion and glucose intolerance in synaptotagmin-7 null mutant mice.
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J. Neurosci. 28, 1949-1960
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Synaptotagmin C2A Loop 2 Mediates Ca2+-dependent SNARE Interactions Essential for Ca2+-triggered Vesicle Exocytosis.
K. L. Lynch, R.R.L. Gerona, E. C. Larsen, R. F. Marcia, J. C. Mitchell, and T.F.J. Martin (2007)
Mol. Biol. Cell 18, 4957-4968
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Complexin 1 knockout mice exhibit marked deficits in social behaviours but appear to be cognitively normal.
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Kinetics of Complexin Binding to the SNARE Complex: Correcting Single Molecule FRET Measurements for Hidden Events.
Y. Li, G. J. Augustine, and K. Weninger (2007)
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Complexin/Synaptotagmin Interplay Controls Acrosomal Exocytosis.
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Dietary Polyunsaturated Fat that Is Low in (n-3) and High in (n-6) Fatty Acids Alters the SNARE Protein Complex and Nitrosylation in Rat Hippocampus.
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J. Nutr. 137, 1852-1856
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Nitric oxide regulation of protein trafficking in the cardiovascular system.
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K. M. Collins and W. T. Wickner (2007)
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VAMP8/Endobrevin as a General Vesicular SNARE for Regulated Exocytosis of the Exocrine System.
C.-C. Wang, H. Shi, K. Guo, C. P. Ng, J. Li, B. Qi Gan, H. Chien Liew, J. Leinonen, H. Rajaniemi, Z. Hong Zhou, et al. (2007)
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From the Cover: Multiple intermediates in SNARE-induced membrane fusion.
T.-Y. Yoon, B. Okumus, F. Zhang, Y.-K. Shin, and T. Ha (2006)
PNAS 103, 19731-19736
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Loss of AP-3 function affects spontaneous and evoked release at hippocampal mossy fiber synapses.
A. Scheuber, R. Rudge, L. Danglot, G. Raposo, T. Binz, J.-C. Poncer, and T. Galli (2006)
PNAS 103, 16562-16567
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Membranes of the world unite!.
L. V. Chernomordik, J. Zimmerberg, and M. M. Kozlov (2006)
J. Cell Biol. 175, 201-207
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Science. ISSN 0036-8075 (print), 1095-9203 (online)