A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer.
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.
DiGiammarino
Enrico L
EL
Department of Structural Biology, St. Jude Children's Research Hospital, 332 N. Lauderdale St., Memphis, Tennessee 38105, USA.
Lee
Amanda S
AS
Cadwell
Craig
C
Zhang
Weixing
W
Bothner
Brian
B
Ribeiro
Raul C
RC
Zambetti
Gerard
G
Kriwacki
Richard W
RW
D018268:Adrenocortical Carcinoma / Q000737:chemistry / Q000453:epidemiology / Q000235:genetics*; D000595:Amino Acid Sequence; D001938:Brazil / Q000453:epidemiology; D002648:Child; D002850:Chromatography, Gel; D002942:Circular Dichroism; D006639:Histidine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D011522:Protons; D055672:Static Electricity; D013696:Temperature; D013816:Thermodynamics; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D011522:Protons; D016159:Tumor Suppressor Protein p53; D006639:Histidine