The C terminus of p53 binds the N-terminal domain of MDM2.

The p53 tumor suppressor interacts with its negative regulator Mdm2 via the former's N-terminal region and core domain, yet the extreme p53 C-terminal region contains lysine residues ubiquitinated by Mdm2 and can bear post-translational modifications that inhibit Mdm2-p53 association. We show that the Mdm2-p53 interaction is decreased upon deletion, mutation ...
or acetylation of the p53 C terminus. Mdm2 decreases the association of full-length but not C-terminally deleted p53 with a DNA target sequence in vitro and in cells. Further, using multiple approaches, we show that a peptide from the p53 C terminus directly binds the Mdm2 N terminus in vitro. We also show that p300-acetylated p53 inefficiently binds Mdm2 in vitro, and Nutlin-3 treatment induces C-terminal modification(s) of p53 in cells, explaining the low efficiency of Nutlin-3 in dissociating p53-MDM2 in vitro.
Mesh Terms:
Animals, Cross-Linking Reagents, DNA, HCT116 Cells, Humans, Imidazoles, Mass Spectrometry, Mice, Models, Biological, Piperazines, Protein Binding, Protein Interaction Mapping, Protein Structure, Tertiary, Proto-Oncogene Proteins c-mdm2, RNA, Small Interfering, Sequence Deletion, Structure-Activity Relationship, Tumor Suppressor Protein p14ARF, Tumor Suppressor Protein p53
Nat. Struct. Mol. Biol.
Date: Aug. 01, 2010
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