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J. Biol. Chem., Vol. 282, Issue 38, 28117-28125, September 21, 2007

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Integration of Inositol Phosphate Signaling Pathways via Human ITPK1^*

Philip P. Chamberlain¹, Xun Qian¹, Amanda R. Stiles^¶, Jaiesoon Cho, David H. Jones, Scott A. Lesley, Elizabeth A. Grabau^¶, Stephen B. Shears², and Glen Spraggon³

From the Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, Inositol Signaling Section, Laboratory of Signal Transduction, NIEHS, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709, and ^¶Department of Plant Pathology, Physiology and Weed Science, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061

Inositol 1,3,4-trisphosphate 5/6-kinase (ITPK1) is a reversible, poly-specific inositol phosphate kinase that has been implicated as a modifier gene in cystic fibrosis. Upon activation of phospholipase C at the plasma membrane, inositol 1,4,5-trisphosphate enters the cytosol and is inter-converted by an array of kinases and phosphatases into other inositol phosphates with diverse and critical cellular activities. In mammals it has been established that inositol 1,3,4-trisphosphate, produced from inositol 1,4,5-trisphosphate, lies in a branch of the metabolic pathway that is separate from inositol 3,4,5,6-tetrakisphosphate, which inhibits plasma membrane chloride channels. We have determined the molecular mechanism for communication between these two pathways, showing that phosphate is transferred between inositol phosphates via ITPK1-bound nucleotide. Intersubstrate phosphate transfer explains how competing substrates are able to stimulate each others' catalysis by ITPK1. We further show that these features occur in the human protein, but not in plant or protozoan homologues. The high resolution structure of human ITPK1 identifies novel secondary structural features able to impart substrate selectivity and enhance nucleotide binding, thereby promoting intersubstrate phosphate transfer. Our work describes a novel mode of substrate regulation and provides insight into the enzyme evolution of a signaling mechanism from a metabolic role.

Received for publication, April 13, 2007 , and in revised form, June 11, 2007.

The atomic coordinates and structure factors (code 2Q7D and 2QB5) 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 based on experiments conducted at beamlines 5.0.3 and 5.0.2 of the Advanced Light Source (ALS). The ALS is supported by the Director, Office of Science, Office of Basic Energy Sciences, Material Sciences Division of the U.S. Department of Energy under contract DE-AC03-76SF00098 at Lawrence Berkeley National Laboratory. This research was in part supported by the Intramural Research Program of the NIEHS, 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.

¹ Both authors contributed equally to this work.

² To whom correspondence may be addressed. E-mail: shears{at}niehs.nih.gov.

³ To whom correspondence may be addressed. E-mail: gspraggo{at}gnf.org.

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