ENGINEERED 4-STRANDED COILED-COIL SUBSTITUTES FOR THE TETRAMERIZATIONDOMAIN OF WILD-TYPE P53 AND ALLEVIATES TRANSDOMINANT INHIBITION BY TUMOR-DERIVED P53 MUTANTS

The tetramerization domain of p53 is required for efficient tumor supp resser activity. This domain, However, also allows wild-type p53 to he tero-oligomerize with dominant negative tumor-derived p53 mutants. We explored the feasibility of substituting the native tetramerization do main of wild-type p53 with an engineered leucine zipper that assembles as a four-stranded coiled coil. The engineered zipper drove p53 tetra merization in vitro and p53 function in vivo. Furthermore, it alleviat ed transdominant inhibition by tumor-derived p53 mutants, implying tha t dominant negative mutants act by hetero-oligomerizing with wild-type p53. The ability of the engineered zipper to drive tetramerization wa s critical for p53 function, since p53 dimers, formed by substituting the p53 tetramerization domain with a native leucine zipper, were weak tumor suppressors.