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Integration of inositol phosphate signaling pathways via human ITPK1.

Chamberlain, Philip and Qian, Xun and Stiles, Amanda and Cho, Jaiesoon and Jones, David and Lesley, Scott and Grabau, Elizabeth and Shears, Stephen and Spraggon, Glen (2007) Integration of inositol phosphate signaling pathways via human ITPK1. The Journal of Biological Chemistry, 282 (38). pp. 28117-28125. ISSN 0021-9258

Abstract

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.

Item Type: Article
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Additional Information: free final full text version available at publisher's official URL and at PubMedCentral; author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
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Date Deposited: 14 Dec 2009 14:05
Last Modified: 31 Jan 2013 01:27
URI: https://oak.novartis.com/id/eprint/114

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