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J. Biol. Chem., Vol. 282, Issue 30, 21786-21797, July 27, 2007

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Doc2 Is a Novel Munc18c-interacting Partner and Positive Effector of Syntaxin 4-mediated Exocytosis^*

From the Department of Biochemistry and Molecular Biology, Center for Diabetes Research, Indiana University School of Medicine, Indianapolis, Indiana 46202

The widely expressed Sec/Munc18 (SM) protein Munc18c is required for SNARE-mediated insulin granule exocytosis from islet beta cells and GLUT4 vesicle exocytosis in skeletal muscle and adipocytes. Although Munc18c function is known to involve binding to the t-SNARE Syntaxin 4, a paucity of Munc18c-binding proteins has restricted elucidation of the mechanism by which it facilitates these exocytosis events. Toward this end, we have identified the double C2 domain protein Doc2 as a new binding partner for Munc18c. Unlike its granule/vesicle localization in neuronal cells, Doc2 was found principally in the plasma membrane compartment in islet beta cells and adipocytes. Moreover, co-immunoprecipitation and GST interaction assays showed Doc2-Munc18c binding to be direct and complexes to be devoid of Syntaxin 4. Supporting the notion of Munc18c binding with Syntaxin 4 and Doc2 in mutually exclusive complexes, in vitro competition with Syntaxin 4 effectively displaced Munc18c from binding to Doc2. The second C2 domain (C2B) of Doc2 and an N-terminal region of Munc18c were sufficient to confer complex formation. Disruption of endogenous Munc18c-Doc2 complexes by addition of the Doc2 binding domain of Munc18c (residues 173–255) was found to selectively inhibit glucose-stimulated insulin release. Moreover, increased expression of Doc2 enhanced glucose-stimulated insulin secretion by 40%, whereas siRNA-mediated depletion of Doc2 attenuated insulin release. All changes in secretion correlated with parallel alterations in VAMP2 granule docking with Syntaxin 4. Taken together, these data support a model wherein Munc18c transiently switches from association with Syntaxin 4 to association with Doc2 at the plasma membrane to facilitate exocytosis.

Received for publication, February 26, 2007 , and in revised form, May 9, 2007.

^* This study was supported by grants from the National Institutes of Health (DK-067912) and the American Diabetes Association (1-03-CD-10) (to D. C. T.), and a postdoctoral fellowship from the American Heart Association (to E. O.). 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.

¹ To whom correspondence should be addressed: 635 Barnhill Dr., MS4053, Dept. of Biochemistry and Molecular Biology, Indianapolis, IN 46202. Tel.: 317-274-1551; Fax: 317-274-4686; E-mail: dthurmon{at}iupui.edu.

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