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Structural basis of the p53 DNA binding domain and PUMA complex

Chang Woo Han1, Han Na Lee1, Mi Suk Jeong2

  • 1Department of Molecular Biology, College of Natural Sciences, Pusan National University, 2Busandaehak-ro 63beon-gil, Geumjeong-gu, Busan, 46241, Republic of Korea.

Biochemical and Biophysical Research Communications
|February 25, 2021
PubMed

Insights

The p53-upregulated modulator of apoptosis (PUMA) peptide directly binds the p53 DNA binding domain. This interaction inhibits lung cancer cell growth, shedding light on p53-mediated apoptosis mechanisms.

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Cancer Research

Background:

  • PUMA is a key mitochondrial protein in p53-mediated apoptosis.
  • p53 induces apoptosis through both transcription-dependent and independent pathways.
  • The transcription-independent interaction between p53 and PUMA is not well understood.

Purpose of the Study:

  • To investigate the direct interaction between the p53 DNA binding domain (DBD) and PUMA.
  • To elucidate the structural basis of the p53 DBD-PUMA interaction.
  • To assess the functional consequence of PUMA binding to p53 DBD in cancer cells.

Main Methods:

  • X-ray crystallography to determine the complex structure.
  • Isothermal titration calorimetry (ITC) for binding affinity.
  • Cell proliferation assays to evaluate functional impact.

Main Results:

  • PUMA peptide binds strongly to the p53 DBD in vitro.
  • The crystal structure revealed PUMA peptide binding to the N-terminal residues of p53 DBD.
  • PUMA peptide demonstrated inhibition of lung cancer cell line growth.

Conclusions:

  • PUMA directly interacts with the p53 DBD, elucidating a transcription-independent apoptotic mechanism.
  • Structural data provides insights into the p53-PUMA complex formation.
  • PUMA peptide exhibits anti-proliferative effects on lung cancer cells, suggesting therapeutic potential.
Keywords:
ApoptosisPumaTumor inhibitionp53

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