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Chan JV, Ping Koh DX, Liu Y, et al. Role of the N-terminal lid in regulating the interaction of phosphorylated MDMX with p53. Oncotarget. 2017;8(68):112825-112840doi: 10.18632/oncotarget.22829.
Chan, J. V., Ping Koh, D. X., Liu, Y., Joseph, T. L., Lane, D. P., Verma, C. S., & Tan, Y. S. (2017). Role of the N-terminal lid in regulating the interaction of phosphorylated MDMX with p53. Oncotarget, 8(68), 112825-112840. https://doi.org/10.18632/oncotarget.22829
Chan, Jane Vin, et al. "Role of the N-terminal lid in regulating the interaction of phosphorylated MDMX with p53." Oncotarget vol. 8,68 (2017): 112825-112840. doi: https://doi.org/10.18632/oncotarget.22829
Chan JV, Ping Koh DX, Liu Y, Joseph TL, Lane DP, Verma CS, Tan YS. Role of the N-terminal lid in regulating the interaction of phosphorylated MDMX with p53. Oncotarget. 2017 Dec 01;8(68):112825-112840. doi: 10.18632/oncotarget.22829. eCollection 2017 Dec 22. PMID: 29348869; PMCID: PMC5762554.
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Oncotarget. 2017 Dec 01;8(68):112825-112840. doi: 10.18632/oncotarget.22829. eCollection 2017 Dec 22.

Role of the N-terminal lid in regulating the interaction of phosphorylated MDMX with p53.

Oncotarget

Jane Vin Chan, Dawn Xin Ping Koh, Yun Liu, Thomas L Joseph, David P Lane, Chandra S Verma, Yaw Sing Tan

Affiliations

  1. Bioinformatics Institute, Agency for Science, Technology and Research (ASTAR), Singapore.
  2. p53 Laboratory, Agency for Science, Technology and Research (ASTAR), Singapore.
  3. Department of Biological Sciences, National University of Singapore, Singapore.
  4. School of Biological Sciences, Nanyang Technological University, Singapore.

PMID: 29348869 PMCID: PMC5762554 DOI: 10.18632/oncotarget.22829

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.

Keywords: MDMX/MDM4; molecular dynamics; p53; phosphotyrosine; protein–protein interaction

Conflict of interest statement

CONFLICTS OF INTEREST None.

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