Structural modulation of p53TAD1-TAZ2 complex upon mutations and post-translational modification

Abstract

The tumour suppressing p53 is a target for genetic alterations in human cancer. Native p53, found in latent state in cells, gets activated following various intracellular or extracellular responses. It plays imperative role in cell-cycle control, via growth-arrest, DNA repair and apoptosis, mainly regulated by post-translational modifications (PTM). However, the influence of PTMs on the activity of p53 is still under extensive experimental and computational study. There are numerous PTM sites in p53, which are reported to regulate its binding affinities with other proteins. Of the many, Thr18 at transactivational domain (TAD) of p53 is reported to amplify p53 activity upon phosphorylation. To understand the molecular basis of p53 recognition by its binding partner upon mutations and PTMs, we have exploited all atom molecular dynamic (MD) simulation of p53TAD1 bound to TAZ2 domain of p300. The MD simulation inferred that phosphorylated and mutated Thr18, as a phospho-mimic, bound with TAZ2, redistributed the charge environment of the interface, thereby modulating the stronger interactions with TAZ2 to enhance the binding efficiency. The electrostatic interactions due to different charge environment together with H-bonding and hydrophobic interaction dictate diverse binding approach between the two. The results of this computational study further explain the importance of the Thr18 as a PTM site in atomistic detail, hence shedding further light to the understanding of how PTMs are imperative for p53 activity to protect the cellular world.

Communicated by Ramaswamy H. Sarma

Keywords:

• p53
• post-translational modification
• phosphorylation
• MD simulation
• mutation
• electrostatic interaction

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

DG acknowledges Department of Biotechnology, Govt. of India for granting Ramalingaswami Fellowship (BT/RLF/Re-entry/52/2012). AG is partially supported from the research grant of the RLS fellowship.