Structural basis for ASPP2 recognition by the tumor suppressor p73

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.