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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
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Structural modulation of p53TAD1-TAZ2 complex upon mutations and post-translational modification.
Anamika Ghosh1, Debabani Ganguly2
1Department of Chemistry, Indian Institute of Engineering Science and Technology, Howrah, India.
Journal of Biomolecular Structure & Dynamics
|November 17, 2021
Summary
Post-translational modifications (PTMs) like phosphorylation at Thr18 amplify tumor suppressor p53 activity. Molecular dynamics simulations reveal how these PTMs enhance p53 binding to partner proteins, crucial for cellular protection.
Area of Science:
- Biochemistry
- Molecular Biology
- Computational Biology
Background:
- The tumor suppressor p53 is frequently altered in human cancers.
- p53 activity is regulated by post-translational modifications (PTMs), including phosphorylation.
- The precise impact of PTMs on p53 binding affinities is under investigation.
Purpose of the Study:
- To elucidate the molecular mechanisms by which PTMs and mutations at Thr18 influence p53 binding to its partners.
- To understand how these modifications affect p53's role in cancer.
Main Methods:
- All-atom molecular dynamic (MD) simulations were employed.
- Simulations focused on the p53 transactivation domain (p53TAD1) bound to the TAZ2 domain of p300.
- Analysis of charge redistribution, electrostatic interactions, H-bonding, and hydrophobic interactions.
Main Results:
- Phosphorylation and mutation at Thr18 act as a phospho-mimic, altering the charge environment at the p53-p300 interface.
- This redistribution enhances binding efficiency between p53TAD1 and TAZ2.
- Electrostatic, H-bonding, and hydrophobic interactions dictate the binding dynamics.
Conclusions:
- Thr18 is a critical PTM site that modulates p53 binding affinity and activity.
- Understanding these atomistic details is vital for comprehending p53's protective cellular functions.
- This study provides insights into how PTMs regulate p53's role in preventing cancer.
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