Flexible lid to the p53-binding domain of human Mdm2: implications for p53 regulation.

The stabilization of p53 against Mdm2-mediated degradation is an important event in DNA damage response. Initial models of p53 stabilization focused on posttranslational modification of p53 that would disrupt the p53-Mdm2 interaction. The N-terminal regions of both p53 and Mdm2 are modified in vivo in response to cellular stress, suggesting ...
that modifications to Mdm2 also may affect the p53-Mdm2 interaction. Our NMR studies of apo-Mdm2 have found that, in addition to Mdm2 residues 25-109 that form the well ordered p53-binding domain that was observed in the p52-Mdm2 complex, Mdm2 residues 16-24 form a lid that closes over the p53-binding site. The Mdm2 lid, which is strictly conserved in mammals, may help to stabilize apo-Mdm2. It also competes weakly with peptidic and nonpeptidic antagonists. Modifications to the Mdm2 lid may disrupt p53-Mdm2 binding leading to p53 stabilization. Mdm2 and Mdm4 possess nearly identical p53-binding domains but different lids suggesting that lid modifications may select for p53 binding.
Mesh Terms:
Amino Acid Sequence, Crystallography, X-Ray, Humans, Models, Molecular, Molecular Sequence Data, Nuclear Magnetic Resonance, Biomolecular, Nuclear Proteins, Protein Binding, Protein Conformation, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-mdm2, Sequence Homology, Amino Acid, Tumor Suppressor Protein p53
Proc. Natl. Acad. Sci. U.S.A.
Date: Feb. 18, 2003
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