The physiologically active form of TP53 is homotetramer, which represents a dimer of dimers (Lee et al. 1994, Clore et al. 1994, Jeffrey et al. 1995), with the dimer considered to represent a transient intermediate (Mateau et al. 1998, Mateau et al. 1999, Natan et al. 2009). The tetramerization domain (TD) of TP53 localizes to the C-terminal region and involves amino acid residues 325-355 and is connected to the DNA binding domain (DBD) via a short unstructured region (reviewed in Wang et al 1993). The destabilizing effects of some of the DBD mutations in TP53 can only be observed in the context of the TP53 tetramer, but not in monomeric TP53 (Lubin et al. 2010). A number of nonsense and frameshift truncations result in mutant TP53 proteins that lack the tetramerization domain. In addition, several missense mutations affect the tetramerization domain, some of which, like R342P and L344P, have been shown to impede tetramerization (Chène and Bechter 1999; Lubin et al. 2010). Oligomerization-defective TP53 TD mutants are considered to be complete loss-of-function mutants in terms of their transcriptional activity, without altered specificity, dominant-negative or gain-of-function effects (Chène and Bechter 1999, reviewed in Chène 2001). However, when overexpressed, some missense TD mutants of TP53 can form homotetramers and heterotetramers with the wild type TP53 which are partially functional and some extent of AS, DN and GOF effects may not be excluded for those mutants (Atz et al. 2000, reviewed in Chène 2001). In addition, the synthetic mutant p153(1-320) which consists of the first 320 amino acids and lacks the TD and the C-terminal domain (CTD), while unable to tetramerize, can form stacked oligomers at the recombinant target gene promoter and induce transcription at a low level. Stacked oligomers are formed through interactions that involve amino acid residues outside the TD, which are facilitated by the presence of a target DNA sequence (Stenger et al. 1994). Recombinant TP53 that consists of amino acid residues 83-323 also predominantly exists as a monomer (reviewed in Wang et al. 1994).
Mastrangelo, IA, Reed, M, Stenger, JE, Hough, PV, Wang, P, Tegtmeyer, P, Mayr, GA, Wang, Y
Reed, M, Mayr, G, Anderson, ME, Schwedes, JF, Stenger, JE, Wang, P, Tegtmeyer, P, Wang, Y
Chène, P
Atz, J, Wagner, P, Roemer, K
Lubin, DJ, Loh, SN, Butler, JS
Bechter, E, Chène, P
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