title: Change in oligomerization specificity of the p53 tetramerization domain by hydrophobic amino acid substitutions.
abstract: The tumor suppressor function of the wild-type p53 protein is transdominantly inhibited by tumor-derived mutant p53 proteins. Such transdominant inhibition limits the prospects for gene therapy approaches that aim to introduce wild-type p53 into cancer cells. The molecular mechanism for transdominant inhibition involves sequestration of wild-type p53 subunits into inactive wild-type/mutant hetero-tetramers. Thus, p53 proteins, whose oligomerization specificity is altered so they cannot interact with tumor-derived mutant p53, would escape transdominant inhibition. Aided by the known three-dimensional structure of the p53 tetramerization domain and by trial and error we designed a novel domain with seven amino acid substitutions in the hydrophobic core. A full-length p53 protein bearing this novel domain formed homo-tetramers and had tumor suppressor function, but did not hetero-oligomerize with tumor-derived mutant p53 and resisted transdominant inhibition. Thus, hydrophobic core residues influence the oligomerization specificity of the p53 tetramerization domain.
authors.affiliation: Programs in Molecular Genetics and Structural Biology, The Wistar Institute, Philadelphia, Pennsylvania 19104-4268, USA.
authors.forename: E S
authors.initials: ES
authors.lastname: Stavridi
authors.forename: N H
authors.initials: NH
authors.lastname: Chehab
authors.forename: L C
authors.initials: LC
authors.lastname: Caruso
authors.forename: T D
authors.initials: TD
authors.lastname: Halazonetis
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D001704:Biopolymers / Q000737:chemistry / Q000235:genetics; D019281:Dimerization; D016147:Genes, Tumor Suppressor; D006801:Humans; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D016133:Polymerase Chain Reaction; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000235:genetics
chemical_list: D001704:Biopolymers; D016159:Tumor Suppressor Protein p53