P53 domain

The monomeric p53 polypeptide chain is divided in three domains... 

The polypeptide chain of p53 is divided in three domains, each with its own function (Figure 9.16). Like many other transcription factors, p53 has an N-terminal activation domain followed by a DNA-binding domain, while the C-terminal 100 residues form an oligomerization domain involved in the formation of the p53 tetramers. Mutants lacking the C-terminal domain do not form tetramers, but the monomeric mutant molecules retain their sequence-specific DNA-binding properties in vitro. 

Figure 9.18 Schematic digram of the structure of the DNA-binding domain of p53. (a) The DNA binding domain of p53 folds into an antiparallel p barrel with long loop regions—...

Figure 9.19 shows the sequence of the DNA that was used for the structure determination of the p53-DNA complex the bases involved in sequence-specific binding to the protein are shaded. One molecule of the DNA-bind-ing domain of p53 binds to the minor and the major grooves of the DNA making sequence-specific interactions with both strands (Figure 9.20). 

Figure 9.19 Nucleotide sequence of the 21-base pair DNA fragment cocrystalUzed with the DNA-binding domain of p53. The p53 binds in a sequence-specific manner to the shaded region.

Jeffrey, P.D., Gorina, S., Pavletich, N.P. Crystal structure of the tetramerization domain of the p53 tumor suppressor at 1.7 Angstroms. Science 267 1498-1502, 1995. 

POU regions bind to DNA by two tandemly oriented helix-turn-helix motifs Much remains to be learnt about the function of homeodomains in vivo Understanding tumorigenic mutations The monomeric p53 polypeptide chain is divided in three domains The oligomerization domain forms tetramers The DNA-binding domain of p53 is an antiparallel P barrel... 

The VACM-1 receptor is a membrane-associated protein with a single putative transmembrane domain that binds selectively AVP (XD — 2 nM), but cannot discriminate between VXR and V2R analogues. It is expressed in endothelial and medullary collecting duct cells and upon stimulation by AVP. It induces a mobilization of cytosolic-free Ca2+, decreases cAMP production and inhibits cellular growth via MAPK phosphorylation and p53 expression. The mechanism of action and physiological functions of this new receptor are not well understood, but it seems to participate in the regulation of AVP induced signal transduction pathways or of a yet unidentified peptide. 

Burton PBJ, Raff MC, Kerr P, Yacoub MH, Barton PJR 1999 An intrinsic timer that controls cell-cycle withdrawal in cultured cardiac myocytes. Dev Biol 216 659—670 Chen X, Ko LJ, Jayaraman L, Prives C 1996 p53 levels, functional domains, and DNA damage determine the extent of the apoptotic response of tumor cells. Genes Dev 10 2438—2451 Duesbery NS, Choi T, Brown KD et al 1997 CENP-E is an essential kinetochore motor in maturing oocytes and is masked during mos-dependent cell cycle arrest at metaphase II. Proc Natl Acad Sci USA 94 9165-9170... 

MDM-2 Loss of p53 binding domain Cancer Tissue Sigalas et al. (1996)... 

Sigalas, I., Calvert, A. H., Anderson, J. J., Neal, D. E., and Lunec, J. (1996). Alternatively spliced mdm2 transcript with loss of p53 binding domain sequences transforming ability and frequent detection in human cancer. Nat. Med. 8, 912-917. 

Also identified during the mid-1990s was the APC (anaphase promoting complex - also known as the cyclosome), another multi-subunit cullin-containing E3 that mediates ubiquitylation of mitotic cyclins [18, 19]. Mdm2, initially thought to be a HECT domain variant, was shown in 1997 to have E3 activity towards p53 in vitro [20]. For the non-HECT E3s no common structural feature had been detected. Thus, by 1997 the only defined molecular signature for E3 activity was the HECT domain. 

In addition to containing protein-protein interaction motifs, E3-substrate specificity may be affected by post-translational modifications. In particular, phosphorylation can alter E3-substrate interactions. One example is p53 where certain phosphorylations inhibit its direct binding to Mdm2, while others indirectly enhance their association by promoting nuclear localization of p53 [104-106]. Phosphorylation also directly enhances substrate interactions, as exemplified by the Cbls, which include phospho-tyrosine binding domains (see below) [107]. 

Honda, R. and H. Yasuda, Activity of MDM2, a ubiquitin ligase, toward p53 or itself is dependent on the RING finger domain of the ligase. Oncogene, 2000, 19(11), 1473-6. 

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