Abstract
Murine double minute 4 protein (MDMX) is crucial for the regulation of the tumor suppressor protein p53. Phosphorylation of the N-terminal domain of MDMX is thought to affect its binding with the transactivation domain of p53, thus playing a role in p53 regulation. In this study, the effects of MDMX phosphorylation on the binding of p53 were investigated using molecular dynamics simulations. It is shown that in addition to the previously proposed mechanism in which phosphorylated Y99 of MDMX inhibits p53 binding through steric clash with P27 of p53, the N-terminal lid of MDMX also appears to play an important role in regulating the phosphorylation-dependent interactions between MDMX and p53. In the proposed mechanism, phosphorylated Y99 aids in pulling the lid into the p53-binding pocket, thus inhibiting the binding between MDMX and p53. Rebinding of p53 appears to be facilitated by the subsequent phosphorylation of Y55, which draws the lid away from the binding pocket by electrostatic attraction of the lid's positively charged N-terminus. The ability to target these mechanisms for the proper regulation of p53 could have important implications for understanding cancer biology and for drug development.
Highlights
The p53 tumor suppressor protein is crucial in protecting our body from diseases such as cancer [1]
MDMX is an inhibitor of p53, and the mechanism by which MDMX releases and rebinds p53 is important for understanding p53 regulation in cancer biology and therapy
Phosphorylation of Y99 on MDMX has been found to impair MDMX–p53 interaction, supposedly due to steric hindrance caused by the phosphate group, while phosphorylation of Y55 on MDMX enhances MDMX–p53 interaction by an unknown mechanism
Summary
The p53 tumor suppressor protein is crucial in protecting our body from diseases such as cancer [1]. When DNA damage occurs, p53 acts as a transcription factor to activate its target genes, resulting in cell cycle arrest and apoptosis. It is normally kept at low levels due to tight regulation by two major inhibitors, mouse double minute 2 and 4 homologs (MDM2 and MDMX respectively, referred to as HDM2 and HDMX in humans), which bind to the transactivation domain of p53 [2] to reduce p53 activity. Following cell repair, the MDM proteins are required to rebind p53 to bring p53 activity back to normal levels. MDMX is required to stabilize MDM2 and prolong its half-life, thereby allowing it to target p53 for degradation, while the nuclear localization sequence of www.impactjournals.com/oncotarget
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