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Human Genetics

, Volume 104, Issue 1, pp 15–22 | Cite as

Disentangling the perturbational effects of amino acid substitutions in the DNA-binding domain of p53

  • A. I. Wacey
  • D. N. Cooper
  • D. Liney
  • E. Hovig
  • M. Krawczak
Original investigation

Abstract

The spectrum of somatic cancer-associated missense mutations in the human TP53 gene was studied in order to assess the potential structural and functional importance of various intra-molecular properties associated with these substitutions. Relating the observed frequency of particular amino acid substitutions in the p53 DNA-binding domain to their expected frequency, as calculated from DNA sequence-dependent mutation rates, yielded estimates of their relative clinical observation likelihood (RCOL). Several biophysical properties were found to display significant covariation with RCOL values. Thus RCOL values were observed to decrease with increasing solvent accessibility of the substituted residue and with increasing distance from the p53 DNA-binding and Zn2+-binding sites. The number of adverse steric interactions introduced by an amino acid replacement was found to be positively correlated with its RCOL value, irrespective of the magnitude of the interactions. A gain in hydrogen bond number was found to be only half as likely to come to clinical attention as mutations involving either a reduction or no change in hydrogen bond number. When the difference in potential energy between the wild-type and mutant DNA-binding domains was considered, RCOL values exhibited a minimum around changes of zero. Finally, classification of mutated residues in terms of their protein/solvent environment yielded, for somatic p53 mutations, RCOL values that resembled those previously determined for inherited mutations of human factor IX causing haemophilia B, suggesting that similar mechanisms may be responsible for the mutation-related perturbation of biological function in different protein folds.

Keywords

Missense Mutation Amino Acid Substitution Significant Covariation Biophysical Property Solvent Accessibility 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer-Verlag Berlin Heidelberg 1999

Authors and Affiliations

  • A. I. Wacey
    • 1
  • D. N. Cooper
    • 2
  • D. Liney
    • 3
  • E. Hovig
    • 4
  • M. Krawczak
    • 2
  1. 1.Computational Biology Unit, Thrombosis Research Institute, London SW3 6LR, UKGB
  2. 2.Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN, UK Tel.: (+44) 1222 744957, Fax: (+44) 1222 747603, e-mail: krawczak@cardiff.ac.ukGB
  3. 3.Computational Biology Laboratory, Beckman Institute, California Institute of Technology, Pasadena, CA 92356, USAUS
  4. 4.Department of Genetics, Institute for Cancer Research, Norwegian Radium Hospital, 0310 Oslo, NorwayNO

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