Structural mechanism of the bromodomain of the coactivator CBP in p53 transcriptional activation.
Lysine acetylation of the tumor suppressor protein p53 in response to a wide variety of cellular stress signals is required for its activation as a transcription factor that regulates cell cycle arrest, senescence, or apoptosis. Here, we report that the conserved bromo-domain of the transcriptional coactivator CBP (CREB binding protein) binds specifically to p53 at the C-terminal acetylated lysine 382. This bromodomain/acetyl-lysine binding is responsible for p53 acetylation-dependent coactivator recruitment after DNA damage, a step essential for p53-induced transcriptional activation of the cyclin-dependent kinase inhibitor p21 in G1 cell cycle arrest. We further present the three-dimensional nuclear magnetic resonance structure of the CBP bromodomain in complex with a lysine 382-acetylated p53 peptide. Using structural and biochemical analyses, we define the molecular determinants for the specificity of this molecular recognition.
Mujtaba
Shiraz
S
Department of Physiology and Biophysics, New York University, 1425 Madison Avenue, New York, NY 10029, USA.
He
Yan
Y
Zeng
Lei
L
Yan
Sherry
S
Plotnikova
Olga
O
Sachchidanand
Sanchez
Roberto
R
Zeleznik-Le
Nancy J
NJ
Ronai
Ze'ev
Z
Zhou
Ming-Ming
MM
D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002453:Cell Cycle; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004249:DNA Damage; D004252:DNA Mutational Analysis; D005347:Fibroblasts / Q000378:metabolism; D016193:G1 Phase; D006801:Humans; D008239:Lysine / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D010957:Plasmids / Q000378:metabolism; D017354:Point Mutation; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000378:metabolism
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016159:Tumor Suppressor Protein p53; D008239:Lysine