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https://hdl.handle.net/10356/88037
Title: | Role of the N-terminal lid in regulating the interaction of phosphorylated MDMX with p53 | Authors: | Chan, Jane Vin Koh, Dawn Xin Ping Liu, Yun Joseph, Thomas L. Lane, David P. Verma, Chandra Shekhar Tan, Yaw Sing |
Keywords: | MDMX/MDM4 Phosphotyrosine |
Issue Date: | 2017 | Source: | Chan, J. V., Koh, D. X. P., Liu, Y., Joseph, T. L., Lane, D. P., Verma, C. S., et al. (2017). Role of the N-terminal lid in regulating the interaction of phosphorylated MDMX with p53. Oncotarget, 8(68), 112825-112840. | Series/Report no.: | Oncotarget | 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. | URI: | https://hdl.handle.net/10356/88037 http://hdl.handle.net/10220/44520 |
DOI: | 10.18632/oncotarget.22829 | Schools: | School of Biological Sciences | Rights: | © 2017 Chan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. | Fulltext Permission: | open | Fulltext Availability: | With Fulltext |
Appears in Collections: | SBS Journal Articles |
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Role of the N-terminal lid in regulating the interaction of phosphorylated MDMX with p53.pdf | 3.1 MB | Adobe PDF | View/Open |
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