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Solution structure of p53 core domain: structural basis for its instability.

José Manuel Pérez Cañadillas1, Henning Tidow, Stefan M V Freund

  • 1Medical Research Council Centre for Protein Engineering, Medical Research Council Centre, Hills Road, Cambridge CB2 2QH, United Kingdom.

Proceedings of the National Academy of Sciences of the United States of America
|February 8, 2006
PubMed
Summary

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The tumor suppressor p53 core domain is unstable. NMR revealed suboptimal hydrogen bonds causing instability, which was reduced by mutation, stabilizing p53.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Molecular Biology

Background:

  • The 25-kDa core domain of tumor suppressor p53 is crucial for its function but inherently unstable, melting near body temperature.
  • This instability makes p53 susceptible to oncogenic mutations that inactivate it by further reducing its stability.

Purpose of the Study:

  • To determine the solution structure of the p53 core domain using advanced NMR spectroscopy.
  • To identify structural features contributing to p53 instability.
  • To investigate the effect of mutations on p53 stability and dynamics.

Main Methods:

  • Nuclear Magnetic Resonance (NMR) spectroscopy with isotopic labeling to determine the structure in solution.
  • Analysis of buried polar groups and hydrogen-bonding networks.

Related Experiment Videos

  • Site-directed mutagenesis to alter specific residues (Tyr-236, Thr-253).

    • Main Results:

    • The solution structure of p53 core domain is similar to its crystal structure but exhibits greater mobility.
    • NMR identified buried hydroxyl and sulfhydryl groups forming suboptimal hydrogen-bond networks, explaining instability.
    • Mutation of Tyr-236/Thr-253 to Phe-236/Ile-253 stabilized p53 by 1.6 kcal/mol.
    • Analysis revealed a mobile loop with potential alternative conformations and dynamic processes related to internal hydrogen bonding.

    Conclusions:

    • p53 core domain instability is linked to suboptimal internal hydrogen bonding.
    • Specific mutations can enhance p53 stability.
    • p53 exhibits inherent dynamics and instability, potentially reflecting evolutionary adaptation.