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MBC in Press, published online ahead of print November 2, 2005
Mol. Biol. Cell 10.1091/mbc.E05-07-0620

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Submitted on July 12, 2005
Revised on September 28, 2005
Accepted on October 25, 2005

Conserved Prefusion Protein Assembly in Regulated Exocytosis

Colin Rickman,*{dagger} José L. Jiménez,{ddagger}{sect} Margaret E. Graham,|| Deborah A. Archer,|| Mikhail Soloviev,¶ Robert D. Burgoyne,|| and Bazbek Davletov*

*MRC Laboratory of Molecular Biology, Cambridge CB2 2QH, United Kingdom; {ddagger}Cancer Research UK London Research Institute, London WC2A 3PX, United Kingdom; {sect}Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom; ||Physiological Laboratory, University of Liverpool, Liverpool L69 3BX, United Kingdom; School of Biological Sciences, Royal Holloway University of London, Egham TW20 0EX, United Kingdom

Monitoring Editor: Benjamin Glick

The regulated release of hormones and neurotransmitters is a fundamental process throughout the animal kingdom. The short timescale for the calcium triggering of vesicle fusion in regulated secretion suggests that the calcium sensor, synaptotagmin, and the SNARE membrane fusion machinery are well ordered before the calcium signal. To gain insight into the organization of the pre-fusion 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 pre-fusion 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 pre-assembled plasma membrane SNARE proteins, before the action of calcium, can provide a precisely-organized ‘tethering’ scaffold that underlies regulated secretion throughout evolution.

{dagger}Present address: Centre for Integrative Physiology, School of Biomedical Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, United Kingdom.

Address correspondence to: Bazbek Davletov (email{at}bazbek.com)




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