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J. Biol. Chem., Vol. 281, Issue 7, 4254-4260, February 17, 2006

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Crystal Structure of the C2 Domain of Class II Phosphatidylinositide 3-Kinase C2^*

Lijun Liu, Xi Song, Dandan He, Chandrasekhar Komma, Akiko Kita, Joseph V. Virbasius^¶, Guiqing Huang^¶, Henry D. Bellamy^||, Kunio Miki, Michael P. Czech^¶, and G. Wayne Zhou¹

From the Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana 70803, Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan, ^¶Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, and the ^||Center for Advanced Microstructures and Devices, Louisiana State University, Baton Rouge, Louisiana 70806

Phosphatidylinositide (PtdIns) 3-kinase catalyzes the addition of a phosphate group to the 3'-position of phosphatidyl inositol. Accumulated evidence shows that PtdIns 3-kinase can provide a critical signal for cell proliferation, cell survival, membrane trafficking, glucose transport, and membrane ruffling. Mammalian PtdIns 3-kinases are divided into three classes based on structure and substrate specificity. A unique characteristic of class II PtdIns 3-kinases is the presence of both a phox homolog domain and a C2 domain at the C terminus. The biological function of the C2 domain of the class II PtdIns 3-kinases remains to be determined. We have determined the crystal structure of the mCPK-C2 domain, which is the first three-dimensional structural model of a C2 domain of class II PtdIns 3-kinases. Structural studies reveal that the mCPK-C2 domain has a typical anti-parallel -sandwich fold. Scrutiny of the surface of this C2 domain has identified three small, shallow sulfate-binding sites. On the basis of the structural features of these sulfate-binding sites, we have studied the lipid binding properties of the mCPK-C2 domain by site-directed mutagenesis. Our results show that this C2 domain binds specifically to PtdIns(3,4)P₂ and PtdIns(4,5)P₂ and that three lysine residues at SBS I site, Lys-1420, Lys-1432, and Lys-1434, are responsible for the phospholipid binding affinity.

Received for publication, October 3, 2005 , and in revised form, November 9, 2005.

The atomic coordinates and structure factors (code 2B3R) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by an American Diabetes Association research grant (to G. W. Z). 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. Tel.: 225-578-6733; Fax: 225-578-8011; E-mail: zhouw{at}lsu.edu.

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