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Originally published in Science Express on 3 May 2007
Science 25 May 2007:
Vol. 316. no. 5828, pp. 1205 - 1208
DOI: 10.1126/science.1142614
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Reports

How Synaptotagmin Promotes Membrane Fusion

Sascha Martens,1 Michael M. Kozlov,2 Harvey T. McMahon1*

Synaptic vesicles loaded with neurotransmitters are exocytosed in a soluble N-ethylmaleimide–sensitive factor attachment protein receptor (SNARE)–dependent manner after presynaptic depolarization induces calcium ion (Ca2+) influx. The Ca2+ sensor required for fast fusion is synaptotagmin-1. The activation energy of bilayer-bilayer fusion is very high ({approx}40 kBT). We found that, in response to Ca2+ binding, synaptotagmin-1 could promote SNARE-mediated fusion by lowering this activation barrier by inducing high positive curvature in target membranes on C2-domain membrane insertion. Thus, synaptotagmin-1 triggers the fusion of docked vesicles by local Ca2+-dependent buckling of the plasma membrane together with the zippering of SNAREs. This mechanism may be widely used in membrane fusion.

1 Medical Research Council–Laboratory of Molecular Biology, Hills Road, CB2 0QH Cambridge, UK.
2 Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel.

* To whom correspondence should be addressed. E-mail: hmm{at}mrc-lmb.cam.ac.uk

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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Ca2+-Dependent, Phospholipid-Binding Residues of Synaptotagmin Are Critical for Excitation-Secretion Coupling In Vivo.
B. E. Paddock, A. R. Striegel, E. Hui, E. R. Chapman, and N. E. Reist (2008)
J. Neurosci. 28, 7458-7466
   Abstract »    Full Text »    PDF »
DOC2B Acts as a Calcium Switch and Enhances Vesicle Fusion.
R. Friedrich, A. J. Groffen, E. Connell, J. R. T. van Weering, O. Gutman, Y. I. Henis, B. Davletov, and U. Ashery (2008)
J. Neurosci. 28, 6794-6806
   Abstract »    Full Text »    PDF »
Specific Lipids Supply Critical Negative Spontaneous Curvature--An Essential Component of Native Ca2+-Triggered Membrane Fusion.
M. A. Churchward, T. Rogasevskaia, D. M. Brandman, H. Khosravani, P. Nava, J. K. Atkinson, and J. R. Coorssen (2008)
Biophys. J. 94, 3976-3986
   Abstract »    Full Text »    PDF »
Mechanism and kinetics of pore formation in membranes by water-soluble amphipathic peptides.
(2008)
PNAS 105, 5087-5092
Membrane Proteins of the Endoplasmic Reticulum Induce High-Curvature Tubules.
J. Hu, Y. Shibata, C. Voss, T. Shemesh, Z. Li, M. Coughlin, M. M. Kozlov, T. A. Rapoport, and W. A. Prinz (2008)
Science 319, 1247-1250
   Abstract »    Full Text »    PDF »
PIKfyve Negatively Regulates Exocytosis in Neurosecretory Cells.
S. L. Osborne, P. J. Wen, C. Boucheron, H. N. Nguyen, M. Hayakawa, H. Kaizawa, P. J. Parker, N. Vitale, and F. A. Meunier (2008)
J. Biol. Chem. 283, 2804-2813
   Abstract »    Full Text »    PDF »
Highlights From The Literature.
(2007)
Physiology 22, 299-302
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Science. ISSN 0036-8075 (print), 1095-9203 (online)