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Oxidation of methionine residue at hydrophobic core destabilizes p53 tetrameric structure

Takao Nomura1, Rui Kamada, Issaku Ito

  • 1Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan.

Biopolymers
|September 11, 2008
PubMed

Insights

Oxidation of methionine in the p53 tumor suppressor protein destabilizes its tetrameric structure. This methionine oxidation may explain how p53 function is inactivated under oxidative stress.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Protein Chemistry

Background:

  • The tumor suppressor protein p53 is crucial for cell cycle regulation and differentiation.
  • p53's tetramerization domain is essential for its function.
  • Protein oxidation can alter protein structure and activity.

Purpose of the Study:

  • To investigate the impact of methionine oxidation at residue 340 (Met340) within the p53 tetramerization domain.
  • To determine how Met340 oxidation affects p53 tetramer stability and oligomerization.

Main Methods:

  • Circular Dichroism (CD) spectroscopy to measure thermal stability (Tm).
  • Gel filtration chromatography to assess oligomerization state.
  • Trypsin digestion assays to evaluate structural integrity.

Main Results:

  • Oxidation of Met340 significantly destabilized the p53 tetramer (22.8 kJ/mol of DeltaDeltaG(Tm)).
  • Oxidation did not alter the overall peptide conformation compared to wild-type.
  • Oxidized Met340 led to a looser local structure, increasing susceptibility to enzymatic degradation.

Conclusions:

  • Oxidation of Met340 in p53 destabilizes the tetrameric structure, potentially through charge repulsion or steric hindrance.
  • Methionine oxidation in p53 may represent a mechanism for inactivating its tumor suppressor functions during oxidative stress.

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