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Structural basis for ASPP2 recognition by the tumor suppressor p73.

Peter Canning1, Frank von Delft, Alex N Bullock

  • 1Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK.

Journal of Molecular Biology
|August 25, 2012
PubMed
Summary

The p73 DNA-binding domain (DBD) structure reveals unique features, including a divergent L2 loop, that influence interactions within the p53 protein family. Understanding these structural variations is key for targeting p53-deficient cancers.

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Area of Science:

  • Molecular Biology
  • Structural Biology
  • Cancer Research

Background:

  • The p53, p63, and p73 protein family are critical stress-responsive transcription factors involved in development and tumor suppression.
  • Most human cancers exhibit loss of p53 function, prompting research into activating p73 for apoptosis in these p53-deficient cancer cells.
  • The p73 DNA-binding domain (DBD) shows resistance to viral oncoproteins and higher thermal stability compared to p53.

Purpose of the Study:

  • To elucidate the structural basis of p73's unique properties and its interactions with other proteins.
  • To understand how structural variations in p73's DBD influence its function and interactions within the p53 family.
  • To investigate the structural complex of the p73 DBD with ASPP2 domains.

Main Methods:

  • High-resolution crystal structure determination of the p73 DBD.
  • Co-crystallization and structural analysis of the p73 DBD complex with ASPP2 ankyrin repeat and SH3 domains.
  • Comparative structural analysis between p73 and p53 DBDs.

Main Results:

  • The crystal structure of the p73 DBD was solved, revealing a conserved architecture with p53 but a distinct L2 loop.
  • A two-residue insertion in the p73 L2 loop alters the protein structure around the p53 mutational hotspot R175.
  • The pro-apoptotic factor ASPP2 binds to p73 through conformational changes in its ankyrin repeat and SH3 domains, preserving the interaction.

Conclusions:

  • Structural variations in the p73 DBD, particularly the L2 loop, differentiate it from p53 and impact protein interactions.
  • The findings highlight the structural plasticity of the p53 family and its interactome.
  • Understanding these structural differences is crucial for developing therapeutic strategies targeting p73 in p53-deficient cancers.