Change in oligomerization specificity of the p53 tetramerization domain by hydrophobic amino acid substitutions

• Published in: Protein science 1999-09, Vol.8 (9), p.1773-1779
• Main Authors: STAVRIDI, ELENA S., CHEHAB, NABIL H., CARUSO, LORETTA C., HALAZONETIS, THANOS D.
• Format: Article
• Language: English
• Subjects: Amino Acid Substitution - genetics; Biopolymers - chemistry; Biopolymers - genetics; Dimerization; Genes, Tumor Suppressor; Humans; hydrophobic effect; Models, Molecular; Mutagenesis, Site-Directed; oligomerization specificity; p53 tumor suppressor; Polymerase Chain Reaction; Protein Conformation; protein design; Protein Structure, Tertiary; Transcription, Genetic; Tumor Suppressor Protein p53 - chemistry; Tumor Suppressor Protein p53 - genetics
• ISSN: 0961-8368; 1469-896X
• DOI: 10.1110/ps.8.9.1773

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.