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Regulation of DNA binding of p53 by its C-terminal domain

Richard L Weinberg1, Stefan M V Freund, Dmitry B Veprintsev

  • 1Cambridge University Chemical Laboratory and Cambridge Centre for Protein Engineering, Medical Research Council Centre, Hills Road, Cambridge CB2 2QH, UK.

Journal of Molecular Biology
|September 3, 2004
PubMed

Insights

The tumor suppressor p53 protein binds DNA directly. Its C-terminal domain regulates this activity by interacting with non-specific DNA sequences, influencing p53

Area of Science:

  • Molecular Biology
  • Protein-DNA Interactions
  • Biochemistry

Background:

  • The tumor suppressor p53 is a critical transcription factor involved in cellular responses to stress.
  • Its C-terminal domain (CTD) is proposed to regulate DNA binding by the core domain, but the mechanism and role of post-translational modifications remain debated.

Purpose of the Study:

  • To investigate the DNA binding activity of unmodified p53 constructs lacking specific domains.
  • To elucidate the regulatory role of the C-terminal domain in p53's interaction with DNA.
  • To identify the specific regions and residues within the CTD involved in DNA binding regulation.

Main Methods:

  • Analysis of DNA binding in solution using various unmodified p53 constructs.
  • Utilizing Nuclear Magnetic Resonance (NMR) spectroscopy to identify protein-DNA interaction sites.

Main Results:

  • The core domain of p53 binds tightly to specific DNA sequences independently of the C-terminal domain.
  • Non-specific DNA sequences bind to the C-terminal domain, inhibiting p53 activity.
  • NMR identified specific C-terminal residues interacting with non-specific DNA, including known post-translationally modified sites.

Conclusions:

  • Unmodified p53 is an active DNA-binding protein.
  • The C-terminal domain plays a direct regulatory role in p53's DNA-binding activity.
  • Post-translational modification sites on the C-terminus are implicated in regulating p53's interaction with non-specific DNA.

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