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 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.
Auguin
Daniel
D
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.
Barthe
Philippe
P
Royer
Catherine
C
Stern
Marc-Henri
MH
Noguchi
Masayuki
M
Arold
Stefan T
ST
Roumestand
Christian
C
D000595:Amino Acid Sequence; D001665:Binding Sites; D004789:Enzyme Activation; D006801:Humans; D007938:Leukemia / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000378:metabolism
C082870:MTCP1 protein, human; D011518:Proto-Oncogene Proteins; C090851:TCL1A protein, human; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt