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Updated: Jun 6, 2025

Purification of Ubiquitinated p53 Proteins from Mammalian Cells
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Purification of Ubiquitinated p53 Proteins from Mammalian Cells

Published on: March 21, 2022

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How does p53 work? Regulation by the intrinsically disordered domains

H Jane Dyson1, Peter E Wright1

  • 1Department of Integrative Structural and Computational Biology, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

Trends in Biochemical Sciences
|November 22, 2024
PubMed

Insights

Tumor suppressor p53 protein defects are common in cancer. Our model shows disordered regions, not just the DNA-binding domain, are key to p53 regulation and activation.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Protein Dynamics

Background:

  • Defects in the tumor suppressor protein p53 are implicated in most human cancers.
  • Research has primarily focused on the DNA-binding domain (DBD) due to frequent cancer mutations within it.
  • The intrinsically disordered N-terminal activation domain (NTAD) and C-terminal regulatory domain (CTD) are increasingly recognized for their regulatory roles.

Purpose of the Study:

  • To propose a mechanistic model for p53 regulation and activation.
  • To highlight the role of intrinsically disordered regions (IDRs) in p53 function.
  • To investigate the interplay between disordered regions and the DNA-binding domain.

Main Methods:

  • Mechanistic modeling of protein interactions.
  • Analysis of intermolecular and intramolecular interactions within p53.
  • Consideration of post-translational modifications (PTMs) in p53 regulation.

Main Results:

  • Intrinsically disordered regions (NTAD and CTD) play a synergistic role with the DBD in p53 regulation.
  • Interactions within and between disordered regions are crucial for p53 activity.
  • Post-translational modifications modulate the interactions of disordered regions, impacting p53 function.

Conclusions:

  • A mechanistic model emphasizing the critical role of disordered regions in p53 regulation and activation is proposed.
  • The study shifts focus from solely the DBD to the integrated function of p53 domains, including IDRs.
  • Understanding the dynamics of disordered regions and PTMs offers new avenues for cancer therapy targeting p53.
Keywords:
DNA bindingDNA damageintrinsically disordered domainspost-translational modificationstranscription factor

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