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Vol. 17, Issue 1, 283-294, January 2006
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* MRC Laboratory of Molecular Biology, Cambridge CB2 2QH, United Kingdom;
Cancer Research UK London Research Institute, London WC2A 3PX, United Kingdom;
Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom;
|| Physiological Laboratory, University of Liverpool, Liverpool L69 3BX, United Kingdom; and
¶ School of Biological Sciences, Royal Holloway University of London, Egham TW20 0EX, United Kingdom
Submitted July 12, 2005;
Revised September 28, 2005;
Accepted October 25, 2005
Monitoring Editor: Benjamin Glick
The regulated release of hormones and neurotransmitters is a fundamental process throughout the animal kingdom. The short time scale for the calcium triggering of vesicle fusion in regulated secretion suggests that the calcium sensor synaptotagmin and the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) membrane fusion machinery are well ordered before the calcium signal. To gain insight into the organization of the prefusion protein assembly in regulated exocytosis, we undertook a structural/functional study of the vesicular synaptotagmin1 and the plasma membrane SNARE proteins, which copurify from the brain in the absence of calcium. Based on an evolutionary analysis, mutagenesis screens, and a computational protein docking approach, we now provide the first testable description of the supramolecular prefusion assembly. Perturbing the determined synaptotagmin/SNARE-interacting interface in several models of regulated exocytosis altered the secretion of hormones and neurotransmitters. These mutations also disrupted the constitutive synaptotagmin/SNARE link in full agreement with our model. We conclude that the interaction of synaptotagmin with preassembled plasma membrane SNARE proteins, before the action of calcium, can provide a precisely organized "tethering" scaffold that underlies regulated secretion throughout evolution.
Present address: Centre for Integrative Physiology, School of Biomedical Sciences, Hugh Robson Bldg., George Square, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom.
Address correspondence to: Bazbek Davletov (email{at}bazbek.com).
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