Structural basis for the co-activation of protein kinase B by T-cell leukemia-1 (TCL1) family proto-oncoproteins

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 PKBβ-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 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.