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

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.