Regulation of membrane fusion by the membrane-proximal coil of the t-SNARE during zippering of SNAREpins

doi:10.1083/jcb.200112081

Published 3 September 2002. doi:10.1083/jcb.200112081

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© The Rockefeller University Press, 0021-9525/2002/9/929 $5.00
The Journal of Cell Biology, Volume 158, Number 5, September 2, 2002 929-940

Article

Regulation of membrane fusion by the membrane-proximal coil of the t-SNARE during zippering of SNAREpins

Thomas J. Melia, Thomas Weber, James A. McNew, Lillian E. Fisher, Robert J. Johnston, Frank Parlati, Lara K. Mahal, Thomas H. Söllner and James E. Rothman

Department of Cellular Biochemistry and Biophysics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021

Address correspondence to James E. Rothman, Dept. of Cellular Biochemistry and Biophysics, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., Box 251, New York, NY 10021. Tel.: (212) 639-8598. Fax: (212) 717-3604. E-mail: j-rothman{at}ski.mskcc.org

We utilize structurally targeted peptides to identify a "t_Cfusion switch" inherent to the coil domains of the neuronalt-SNARE that pairs with the cognate v-SNARE. The t_C fusion switchis located in the membrane-proximal portion of the t-SNARE andcontrols the rate at which the helical bundle that forms theSNAREpin can zip up to drive bilayer fusion. When the fusionswitch is "off" (the intrinsic state of the t-SNARE), zipperingof the helices from their membrane-distal ends is impeded andfusion is slow. When the t_C fusion switch is "on," fusion ismuch faster. The t_C fusion switch can be thrown by a peptidethat corresponds to the membrane-proximal half of the cognatev-SNARE, and binds reversibly to the cognate region of the t-SNARE.This structures the coil in the membrane-proximal domain ofthe t-SNARE and accelerates fusion, implying that the intrinsicallyunstable coil in that region is a natural impediment to thecompletion of zippering, and thus, fusion. Proteins that stabilizeor destabilize one or the other state of the t_C fusion switchwould exert fine temporal control over the rate of fusion afterSNAREs have already partly zippered up.

Key Words: SNAP-25; liposome; syntaxin; vesicle; VAMP

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