Role of the N-terminal lid in regulating the interaction of phosphorylated MDMX with p53
Metrics: PDF 787 views | HTML 2075 views | ?
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
Chandra S. Verma, email: email@example.com
Yaw Sing Tan, email: firstname.lastname@example.org
Keywords: MDMX/MDM4; phosphotyrosine; p53; protein–protein interaction; molecular dynamics
Received: August 03, 2017 Accepted: October 05, 2017 Published: December 01, 2017
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.