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Deciphering the mechanism of p73 recognition of p53 response elements using the crystal structure of p73-DNA

Tirthankar Koley1, Sanghati Roy Chowdhury1, Tushar Kushwaha1

  • 1Department of Biophysics, All India Institute of Medical Sciences, New Delhi 110029, India.

International Journal of Biological Macromolecules
|February 26, 2022
PubMed

Insights

The p73 transcription factor

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Genetics

Background:

  • p73 is a p53 family transcription factor regulating critical cellular processes.
  • p73's role in gene regulation, particularly in cell fate and neuronal development, is complex.
  • The precise mechanism of p73's DNA response element (RE) selectivity remains unclear.

Purpose of the Study:

  • To elucidate the molecular basis of p73's recognition of DNA response elements (REs).
  • To understand how p73 achieves selectivity for diverse target genes.
  • To investigate the structural mechanisms underlying p73's transcriptional regulation.

Main Methods:

  • X-ray crystallography of the p73 DNA binding domain (DBD) complexed with a DNA sequence.
  • Molecular dynamics simulations using natural p53 promoter sequences.
  • Analysis of protein-DNA interactions and structural determinants of selectivity.

Main Results:

  • The crystal structure reveals p73 DBD complexed with a 12-bp DNA sequence.
  • Molecular dynamics simulations show distinct DNA conformations and p73 interactions with natural promoters.
  • Key residues Lys138 and Arg268, along with DNA groove variations, mediate sequence-specific recognition.
  • DNA structural features and half-site spacing dictate p73 tetramerization and transactivation.

Conclusions:

  • p73 exhibits unique tetramerization and DNA binding modes dependent on promoter sequence and structure.
  • The findings provide molecular insights into p73's transcriptional regulation of cell fate and development genes.
  • Understanding p73-DNA interactions is crucial for deciphering its role in biological processes.
Keywords:
Crystal structureGene transcriptionMolecular dynamicsResponse elementp53p73

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