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J. Biol. Chem., Vol. 281, Issue 40, 29597-29605, October 6, 2006

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Lipidic Antagonists to SNARE-mediated Fusion^*

From the Department of Physiology and Cellular Biophysics, Columbia University, College of Physicians and Surgeons, New York, New York 10032

SNARE proteins mediate the fusion of lipid bilayers by the directed assembly of coiled-coil domains arising from apposing membranes. We have utilized inverted cone-shaped lipids, antagonists of the necessary membrane deformation during fusion to characterize the extent and range of SNARE assembly up to the moment of stalk formation between bilayers. The inverted cone-shaped lipid family of acyl-CoAs specifically inhibits the completion of fusion in an acyl-chain length-dependent manner. Removal of acyl-CoA from the membrane relieves the inhibition and initiates a burst of membrane fusion with rates exceeding any point in the control curves lacking acyl-CoA. This burst indicates the accumulation of semi-assembled fusion complexes. These preformed complexes are resistant to cleavage by botulinum toxin B and thus appear to have progressed beyond the "loosely zippered" state of docked synaptic vesicles. Surprisingly, application of the soluble domain of VAMP2, which blocks SNARE assembly by competing for binding on the available t-SNAREs, blocks recovery from the acyl-CoA inhibition. Thus, complexes formed in the presence of a lipidic antagonist to fusion are incompletely assembled, suggesting that the formation of tightly assembled SNARE pairs requires progression all the way through to membrane fusion. In this regard, physiologically docked exocytic vesicles may be anchored by a highly dynamic and potentially even reversible SNAREpin.

Received for publication, February 24, 2006 , and in revised form, August 2, 2006.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

² Present address: Genomics Core Facility, Dept of Molecular Biology, Memorial Sloan Kettering Cancer Center, 430 E. 67th St., New York, NY 10021.

¹ To whom correspondence should be addressed: Dept. of Physiology and Cellular Biophysics, Columbia University, 1150 Saint Nicholas Ave., New York, NY 10032. Tel.: 212-851-5569; Fax: 212-851-5570; E-mail: tm2176{at}columbia.edu.

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