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Papers In Press, published online ahead of print November 30, 2001
J. Biol. Chem, 10.1074/jbc.M110775200
Submitted on November 9, 2001
Revised on November 29, 2001
Accepted on November 30, 2001

Stereospecific substrate recognition by phosphatidylinositol phosphate kinases is swapped by changing a single amino acid residue

Jeannette Kunz, Allison Fuelling, Lottie Kolbe, and Richard A. Anderson

Pharmacology, University of Wisconsin Medical School, Madision, WI 53706

Corresponding Author: raanders{at}facstaff.wisc.edu

Type I and type II phosphatidylinositol phosphate (PIP) kinases generate the lipid second messenger PtdIns(4,5)P2 and thus play fundamental roles in the regulation of many cellular processes. Although the two kinase families are highly homologous, they phosphorylate distinct substrates and are functionally non-redundant. Type I PIP kinases phosphorylate PtdIns(4)P at the D-5 hydroxyl group and are consequently PtdIns(4)P 5-kinases. By contrast, type II PIP kinases are PtdIns(5)P 4-kinases that phosphorylate PtdIns(5)P at the D-4 position. Type I PIP kinases, in addition, also phosphorylate other phosphoinositides in vitro and in vivo and thus have the potential to generate multiple lipid second messengers. To understand how these enzymes differentiate between stereo-isomeric substrates we used a site-directed mutagenesis approach. Here, we show that a single amino acid substitution in the activation loop, A381E in IIbeta and the corresponding mutation E362A in Ibeta , is sufficient to swap substrate specificity between these PIP kinases. In addition to its role in substrate specificity the type I activation loop is also key in subcellular targeting. The Ibeta (E362A) mutant and other mutants with reduced PtdIns(4)P binding affinity were largely cytosolic when expressed in mammalian cells in contrast to wild-type Ibeta which targets to the plasma membrane. These results clearly establish the role of the activation loop in determining both signaling specificity and plasma membrane targeting of type I PIP kinases.


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