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Yeast As a Chassis for Developing Functional Assays to Study Human P53
14:57

Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

Mechanism of DNA-binding loss upon single-point mutation in p53

Jon D Wright1, Carmay Lim

  • 1Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan, ROC.

Journal of Biosciences
|October 5, 2007
PubMed

Insights

Mutations in the p53 core domain (p53c) reduce DNA binding in over half of human cancers. Loss of the Asp 281 salt bridge, not just direct contacts, explains this reduced binding affinity for cancer-associated mutations.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Structural Biology

Background:

  • Over 50% of human cancers harbor mutations in the p53 tumor suppressor protein.
  • Mutations frequently occur in the p53 core domain (p53c), impairing sequence-specific DNA binding.
  • The precise mechanisms underlying loss of DNA binding affinity and specificity due to p53c mutations are not fully understood.

Purpose of the Study:

  • To investigate the molecular factors responsible for the loss of DNA binding in p53c upon substitution of Arginine 273 (Arg 273) to Histidine (His) or Cysteine (Cys).
  • To elucidate the role of specific residues and structural changes in mediating the functional consequences of common cancer-associated p53 mutations.

Main Methods:

  • Computational analysis of free energies for wild-type and mutant p53c binding to DNA.
  • Decomposition of binding free energies to identify contributions from individual amino acid residues.
  • Analysis of structural changes and salt-bridge interactions.

Main Results:

  • The loss of DNA binding affinity upon Arg 273 mutation (to His or Cys) is attributed to both direct loss of contacts with DNA phosphates and indirect, longer-range structural alterations.
  • A critical salt bridge involving Aspartic acid 281 (Asp 281) was identified as a key factor in maintaining p53c DNA binding.
  • Mutation of Arg 273 disrupts the Asp 281 salt bridge, leading to significant changes in protein-DNA interaction.

Conclusions:

  • Asp 281 plays a crucial role in p53c sequence-specific DNA binding by correctly positioning key residues like Arg 273 and Arg 280.
  • The integrity of the Asp 281 salt bridge is essential for maintaining the optimal protein conformation required for DNA binding.
  • Understanding these mechanisms provides insights into p53 dysfunction in cancer and potential therapeutic strategies.

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