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.
Mesh Terms:
Amino Acid Sequence, Animals, Blotting, Western, COS Cells, Cell Cycle, Cell Line, Cyclin-Dependent Kinase Inhibitor p21, Cyclins, DNA Damage, DNA Mutational Analysis, Fibroblasts, G1 Phase, Humans, Lysine, Magnetic Resonance Spectroscopy, Mice, Models, Molecular, Molecular Sequence Data, NIH 3T3 Cells, Plasmids, Point Mutation, Protein Binding, Protein Conformation, Protein Structure, Secondary, Protein Structure, Tertiary, Sequence Homology, Amino Acid, Transcriptional Activation, Tumor Suppressor Protein p53
Mol. Cell
Date: Jan. 30, 2004
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