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Flexible lid to the p53-binding domain of human Mdm2: implications for p53 regulation
Mark A McCoy1, Jennifer J Gesell, Mary M Senior
1Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. mark.mccoy@spcorp.com
Abstract:
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.
Insights
Stabilizing the tumor suppressor p53 (also known as p53) is key in DNA damage response. New findings reveal a conserved "lid" region on Mdm2 that regulates p53 binding and stabilization.
Area of Science:
- Molecular Biology
- Biochemistry
- Structural Biology
Background:
- p53 stabilization is crucial for DNA damage response.
- Previous models focused on p53 modifications affecting p53-Mdm2 interaction.
- Cellular stress modifies N-terminal regions of both p53 and Mdm2.
Purpose of the Study:
- Investigate Mdm2 modifications' role in p53 stabilization.
- Characterize the structural role of Mdm2 in regulating p53 binding.
Main Methods:
- Nuclear Magnetic Resonance (NMR) studies of apo-Mdm2.
- Structural analysis of Mdm2 residues 16-24 (the lid) and residues 25-109 (p53-binding domain).
Main Results:
- Identified a novel Mdm2 lid structure (residues 16-24) that covers the p53-binding site.
- This lid is conserved in mammals and may stabilize apo-Mdm2.
- Lid modifications could disrupt p53-Mdm2 binding, leading to p53 stabilization.
- Mdm2 and Mdm4 have similar binding domains but different lids, suggesting selective p53 binding.
Conclusions:
- The Mdm2 lid is a critical regulatory element in p53-Mdm2 interaction.
- Targeting the Mdm2 lid offers a potential strategy for p53 stabilization in cancer therapy.
- Structural differences in Mdm2 lids may influence p53 binding specificity.