Abstract
The p53 protein is the major tumor suppressor in mammals. The discovery of the p53 homologs p63 and p73 defined a family of p53 members with distinct roles in tumor suppression, differentiation, and development. Here, we describe the biochemical characterization of the core DNA-binding domain of a human isoform of p63, p63-delta, and particularly novel features in comparison with p53. In contrast to p53, the free p63 core domain did not show specific binding to p53 DNA consensus sites. However, glutathione S-transferase-fused and thus dimerized p63 and p53 core domains had similar affinity and specificity for the p53 consensus sites p21, gadd45, cyclin G, and bax. Furthermore, the fold of p63 core was remarkably stable compared with p53 as judged by differential scanning calorimetry (T(m) = 61 degrees C versus 44 degrees C for p53) and equilibrium unfolding ([urea](50%) = 5.2 m versus 3.1 m for p53). A homology model of p63 core highlights differences at a segment near the H1 helix hypothetically involved in the formation of the dimerization interface in p53, which might reduce cooperativity of p63 core DNA binding compared with p53. The model also shows differences in the electrostatic and hydrophobic potentials of the domains relevant to folding stability.
Highlights
The tumor suppressor gene p53 is the most frequent site of genetic alterations found in human tumors [1]
A homology model of p63 core highlights differences at a segment near the H1 helix hypothetically involved in the formation of the dimerization interface in p53, which might reduce cooperativity of p63 core DNA binding compared with p53
The isolated tetramerization domain forms a symmetric dimer of dimers [72,73,74], and two contrasting models have been proposed to describe how the DNA-binding domain (DBD) of each dimer are bound to the quarter-sites, namely with either consecutive or alternating arrangements [75]
Summary
The tumor suppressor gene p53 is the most frequent site of genetic alterations found in human tumors [1]. Several studies showed that some isoforms of p63 and p73 can bind to p53-responsive elements, transactivate p53-responsive genes, and induce apoptosis upon overexpression [7, 10, 11, 17]. This structural and functional homology defined a new superfamily of transcription factors, in which p63 and p73 seem to be ancestral genes of the phylogenetically younger p53. Unlike p53, p63 is essential for embryonic development; mice lacking the p63 gene exhibit severe defects in ectodermal differentiation [20] Based on this phenotype, a role for p63 in stem cell regeneration to sustain epithelial development was suggested [22]. Mutations in the p63 DNA-binding domain are the cause of the autosomal dominant EEC1 syndrome and the EEC-like limb mammary syndrome [23]
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