Oncotarget

Research Papers:

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

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

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Oncotarget. 2017; 8:112825-112840. https://doi.org/10.18632/oncotarget.22829

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Abstract

Jane Vin Chan1,*, Dawn Xin Ping Koh1,*, Yun Liu1, Thomas L. Joseph1, David P. Lane2, Chandra S. Verma1,3,4 and Yaw Sing Tan1

1Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), Singapore

2p53 Laboratory, Agency for Science, Technology and Research (A*STAR), Singapore

3Department of Biological Sciences, National University of Singapore, Singapore

4School of Biological Sciences, Nanyang Technological University, Singapore

*These authors contributed equally to this work

Correspondence to:

Chandra S. Verma, email: chandra@bii.a-star.edu.sg

Yaw Sing Tan, email: tanys@bii.a-star.edu.sg

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

Received: August 03, 2017     Accepted: October 05, 2017     Published: December 01, 2017

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.


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