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 Arold*, Christian Roumestand

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

Chromosomal translocations leading to overexpression of p14TCL1 and its homologue p13MTCP1 are hallmarks of several human T-cell malignancies (1). p14TCL1/ p13MTCP1 co-activate protein kinase B (PKB, also named Akt) by binding to its pleckstrin homology (PH) domain, suggesting that p14TCL1/p13MTCP1 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 PKBβ-PH and p14TCL1/p13 MTCP1. We show that p14TCL1/p13MTCP1 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 cross-linking 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.

Original languageEnglish (US)
Pages (from-to)35890-35902
Number of pages13
JournalJournal of Biological Chemistry
Volume279
Issue number34
DOIs
StatePublished - Aug 20 2004

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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