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J. Biol. Chem., Vol. 278, Issue 28, 26265-26274, July 11, 2003

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Ca²⁺-dependent Phosphorylation of Syntaxin-1A by the Death-associated Protein (DAP) Kinase Regulates Its Interaction with Munc18^*

Jin-Hua Tian, Sunit Das and Zu-Hang Sheng 

From the Synaptic Function Unit, NINDS, National Institutes of Health, Bethesda, Maryland 20892-4154

Syntaxin-1 is a key component of the synaptic vesicle docking/fusion machinery that binds with VAMP/synaptobrevin and SNAP-25 to form the SNARE complex. Modulation of syntaxin binding properties by protein kinases could be critical to control of neurotransmitter release. Using yeast two-hybrid selection with syntaxin-1A as bait, we have isolated a cDNA encoding the C-terminal domain of death-associated protein (DAP) kinase, a calcium/calmodulin-dependent serine/threonine protein kinase. Expression of DAP kinase in adult rat brain is restricted to particular neuronal subpopulations, including the hippocampus and cerebral cortex. Biochemical studies demonstrate that DAP kinase binds to and phosphorylates syntaxin-1 at serine 188. This phosphorylation event occurs both in vitro and in vivo in a Ca²⁺-dependent manner. Syntaxin-1A phosphorylation by DAP kinase or its S188D mutant, which mimics a state of complete phosphorylation, significantly decreases syntaxin binding to Munc18-1, a syntaxin-binding protein that regulates SNARE complex formation and is required for synaptic vesicle docking. Our results suggest that syntaxin is a DAP kinase substrate and provide a novel signal transduction pathway by which syntaxin function could be regulated in response to intracellular [Ca²⁺] and synaptic activity.

Received for publication, January 16, 2003 , and in revised form, April 30, 2003.

^* This work was supported by the intramural research program of NINDS, National Institutes of Health. 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.

To whom correspondence should be addressed: Synaptic Function Unit, NINDS, National Institutes of Health, Bldg. 36, Rm. 5A23, 36 Convent Dr., Bethesda, MD 20892-4154. Tel.: 301-435-4596; E-mail: shengz{at}ninds.nih.gov.

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