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MBC in Press, published online ahead of print November 14, 2007
Mol. Biol. Cell 10.1091/mbc.E07-02-0148

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Submitted on February 21, 2007
Revised on October 29, 2007
Accepted on November 5, 2007

SNARE-catalyzed Fusion Events Are Regulated by Syntaxin1A–Lipid Interactions

Alice D. Lam,*{dagger} Petra Tryoen-Toth,{ddagger} Bill Tsai,{sect} Nicolas Vitale,{ddagger} and Edward L. Stuenkel*{dagger}

*Department of Molecular and Integrative Physiology, {dagger}Neuroscience Program, and {sect}Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109; {ddagger}Département Neurotransmission et Sécrétion Neuroendocrine, Unité Mixte de Recherche 7168/LC2, Centre National de la Recherche Scientifique/Université Louis Pasteur, 67070 Strasbourg, France

Monitoring Editor: Patrick Brennwald

Membrane fusion is a process that intimately involves both proteins and lipids. While the SNARE proteins, which ultimately overcome the energy barrier for fusion, have been extensively studied, regulation of the energy barrier itself, determined by specific membrane lipids, has been largely overlooked. Our findings reveal a novel function for SNARE proteins in reducing the energy barrier for fusion, by directly binding and sequestering fusogenic lipids to sites of fusion. We demonstrate a specific interaction between Syntaxin1A and the fusogenic lipid phosphatidic acid, in addition to multiple polyphosphoinositide lipids, and define a polybasic juxtamembrane region within Syntaxin1A as its lipid binding domain. In PC-12 cells, Syntaxin1A mutations that progressively reduced lipid binding resulted in a progressive reduction in evoked secretion. Moreover, amperometric analysis of fusion events driven by a lipid binding-deficient Syntaxin1A mutant (5RK/A) demonstrated alterations in fusion pore dynamics suggestive of an energetic defect in secretion. Overexpression of the phosphatidic acid-generating enzyme, phospholipase D1, completely rescued the secretory defect seen with the 5RK/A mutant. Moreover, knockdown of phospholipase D1 activity drastically reduced control secretion, while leaving 5RK/A-mediated secretion relatively unaffected. Altogether, these data suggest that Syntaxin1A-lipid interactions are a critical determinant of the energetics of SNARE-catalyzed fusion events.

Address correspondence to: Alice D. Lam (adlam{at}umich.edu)




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