Structural basis for the co-activation of protein kinase B by T-cell leukemia-1 (TCL1) family proto-oncoproteins.
Auguin, Daniel, et al.
J. Biol. Chem., 279: 35890-902 (2004)
2004
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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 PKBbeta-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. | 15169787
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TCL1: a new drug target in lymphoid and germ-cell malignancies?
Lock, Richard B
Int. J. Biochem. Cell Biol., 35: 1614-8 (2003)
2003
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The protein product of the T-cell leukemia/lymphoma 1 (TCL1) oncogene was recently identified as a novel Akt kinase activator. Its crystal structure predicts regions most likely involved in protein-protein interactions, and complex formation is required for TCL1 to activate Akt. TCL1 is expressed in a broad range of normal and malignant lymphoid cell types and in a high proportion of testicular seminomas of germ cell origin, indicating its potential to serve as a novel anti-cancer drug target. This review is focused on the current state of knowledge of TCL1 and the medical implications of its discovery. | 12962701
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Crystal structures of Tcl1 family oncoproteins and their conserved surface features.
Petock, John M, et al.
ScientificWorldJournal, 2: 1876-84 (2002)
2002
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Members of the TCL1 family of oncogenes are abnormally expressed in mature T-cell leukemias and B-cell lymphomas. The proteins are involved in the coactivation of protein kinase B (Akt/PKB), a key intracellular kinase. The sequences and crystal structures of three Tcl1 proteins were analyzed in order to understand their interactions with Akt/PKB and the implications for lymphocyte malignancies. Tcl1 proteins are approximately 15 kD and share 25-80% amino acid sequence identity. The tertiary structures of mouse Tcl1, human Tcl1, and Mtcp1 are very similar. Analysis of the structures revealed conserved semi-planar surfaces that have characteristics of surfaces involved in protein-protein interactions. The Tcl1 proteins show differences in surface charge distribution and oligomeric state suggesting that they do not interact in the same way with Akt/PKB and other cellular protein(s). | 12920316
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