Dual-site regulation of MDM2 E3-ubiquitin ligase activity.
The control of p53 ubiquitination by MDM2 provides a model system to define how an E3-ligase functions on a conformationally flexible substrate. The mechanism of MDM2-mediated ubiquitination of p53 has been analyzed by deconstructing, in vitro, the MDM2-dependent ubiquitination reaction. Surprisingly, ligands binding to the hydrophobic cleft of MDM2 do ... not inhibit its E3-ligase function. However, peptides from within the DNA binding domain of p53 that bind the acid domain of MDM2 inhibit ubiquitination of p53, localizing a motif that harbors a key ubiquitination signal. The binding of ligands to the N-terminal hydrophobic cleft of MDM2 reactivates, in vitro and in vivo, MDM2-catalyzed ubiquitination of p53F19A, a mutant p53 normally refractory to MDM2-catalyzed ubiquitination. We propose a model in which the interaction between the p53-BOX-I domain and the N terminus of MDM2 promotes conformational changes in MDM2 that stabilize acid-domain interactions with a ubiquitination signal in the DNA binding domain of the p53 tetramer.
Mesh Terms:
Amino Acid Sequence, Cells, Cultured, Ligands, Models, Biological, Molecular Sequence Data, Protein Binding, Protein Structure, Tertiary, Proto-Oncogene Proteins c-mdm2, Retinoblastoma Protein, Tumor Suppressor Protein p53, Ubiquitin-Protein Ligases
Amino Acid Sequence, Cells, Cultured, Ligands, Models, Biological, Molecular Sequence Data, Protein Binding, Protein Structure, Tertiary, Proto-Oncogene Proteins c-mdm2, Retinoblastoma Protein, Tumor Suppressor Protein p53, Ubiquitin-Protein Ligases
Mol. Cell
Date: Jul. 21, 2006
PubMed ID: 16857591
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