title: Conformational effects of environmentally induced, cancer-related mutations in the p53 protein.
abstract: The tumor suppressor gene p53 has been identified as the most frequent target of genetic alterations in human cancers. A considerable number of environmentally induced, cancer-related p53 mutations in human tumors have been found in a highly conserved proline-rich sequence of the p53 protein encompassed by amino acid residues 147-158. Using conformational energy analysis based on ECEPP (Empirical Conformational Energy for Peptides Program), we have determined the low-energy three-dimensional structures for this dodecapeptide sequence for the human wild-type p53 protein and three environmentally induced, cancer-related mutant p53 proteins with His-151, Ser-152, and Val-154, respectively. The results suggest that the wild-type sequence adopts a well-defined low-energy conformation and that the mutant peptides adopt well-defined conformations that are distinctly different from the conformation of the wild-type peptide. These results are consistent with experimental conformational studies demonstrating altered detectability of antigenic epitopes in wild-type and mutant p53 proteins. These results suggest that the oncogenic effects of these environmentally induced, cancer-related, mutant p53 proteins may be mediated by distinct local conformational changes in the protein.
authors.affiliation: Department of Medicine and Comprehensive Cancer Center, Columbia University, New York, NY 10032.
authors.forename: P W
authors.initials: PW
authors.lastname: Brandt-Rauf
authors.forename: R
authors.initials: R
authors.lastname: Monaco
authors.forename: M R
authors.initials: MR
authors.lastname: Pincus
mesh_terms: D000595:Amino Acid Sequence; D017124:Conserved Sequence; D016158:Genes, p53; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D011336:Probability; D011487:Protein Conformation; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000235:genetics
chemical_list: D016159:Tumor Suppressor Protein p53