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J. Biol. Chem., Vol. 279, Issue 34, 35890-35902, August 20, 2004

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Structural Basis for the Co-activation of Protein Kinase B by T-cell Leukemia-1 (TCL1) Family Proto-oncoproteins^*

Daniel Auguin, Philippe Barthe, Catherine Royer, Marc-Henri Stern, Masayuki Noguchi¶, Stefan T. Arold||, and Christian Roumestand||

From the Centre de Biochimie Structurale, UMR 5048 CNRS/UM1-UMR 554 INSERM/UM1, Faculté de Pharmacie, BP14491, 15 Avenue Charles Flahault, 34093 Montpellier Cedex 5, France, Unité INSERM U509, Institut Curie, Section de Recherche, 26 rue d'Ulm, F75248 Paris Cedex 5, France, and ^¶Division of Cancer Biology, Institute for Genetic Medicine, Hokkaido University, N15 W7, Kita-ku, Sapporo 060-0815, Japan

Chromosomal translocations leading to overexpression of p14^TCL1 and its homologue p13^MTCP1 are hallmarks of several human T-cell malignancies (1). p14^TCL1/p13^MTCP1 co-activate protein kinase B (PKB, also named Akt) by binding to its pleckstrin homology (PH) domain, suggesting that p14^TCL1/p13^MTCP1 induce T-cell leukemia by promoting anti-apoptotic signals via PKB (2, 3). Here we combined fluorescence anisotropy, NMR, and small angle x-ray-scattering measurements to determine the affinities, molecular interfaces, and low resolution structure of the complex formed between PKB-PH and p14^TCL1/p13^MTCP1. We show that p14^TCL1/p13^MTCP1 target PKB-PH at a site that has not yet been observed in PH-protein interactions. Located opposite the phospholipid binding pocket and distal from known protein-protein interaction sites on PH domains, the binding of dimeric TCL1 proteins to this site would allow the crosslinking of two PKB molecules at the cellular membrane in a preactivated conformation without disrupting certain PH-ligand interactions. Thus this interaction could serve to strengthen membrane association, promote trans-phosphorylation, hinder deactivation of PKB, and involve PKB in a multi-protein complex, explaining the array of known effects of TCL1. The binding sites on both proteins present attractive drug targets against leukemia caused by TCL1 proteins.

Received for publication, January 13, 2004 , and in revised form, April 30, 2004.

^* This work was supported in part by a research grant from the "Association pour la Recherche sur le Cancer," the "Fondation pour la Recherche Medicale" (to D. A.), and a cancer research investigator award and a grant-in-aid from the Ministry of Education, Science and Technology (Japan) (to M. N.). 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.

The on-line version of this article (available at http://www.jbc.org) contains Supplemental Material 1 and 2.

^|| To whom correspondence may be addressed. E-mail: roume{at}cbs.cnrs.fr (C. Roumestand) and stef{at}cbs.cnrs.fr (S. T. A.).

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