A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer

Nat Struct Biol. 2002 Jan;9(1):12-6. doi: 10.1038/nsb730.


The p53 tumor suppressor requires tetramerization to function as an initiator of cell cycle arrest and/or apoptosis. Children in southern Brazil that exhibit an elevated incidence of adrenocortical carcinoma (ACC) harbor an Arg 337 to His mutation within the tetramerization domain of p53 (p53-R337H; 35 of 36 patients). The mutant tetramerization domain (p53tet-R337H) adopts a native-like fold but is less stable than the wild type domain (p53tet-wt). Furthermore, the stability of p53tet-R337H is highly sensitive to pH in the physiological range; this sensitivity correlates with the protonation state of the mutated His 337. These results demonstrate a pH-sensitive molecular defect of p53 (R337H), suggesting that pH-dependent p53 dysfunction is the molecular basis for these cases of ACC in Brazilian children.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adrenocortical Carcinoma / chemistry
  • Adrenocortical Carcinoma / epidemiology
  • Adrenocortical Carcinoma / genetics*
  • Amino Acid Sequence
  • Brazil / epidemiology
  • Child
  • Chromatography, Gel
  • Circular Dichroism
  • Histidine / chemistry
  • Histidine / genetics
  • Histidine / metabolism
  • Humans
  • Hydrogen-Ion Concentration
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation, Missense / genetics*
  • Protein Structure, Quaternary
  • Protein Structure, Tertiary
  • Protons
  • Static Electricity
  • Temperature
  • Thermodynamics
  • Tumor Suppressor Protein p53 / chemistry*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*


  • Protons
  • Tumor Suppressor Protein p53
  • Histidine