| Literature References | 1. CLORE, G.M., ERNST, J., CLUBB, R., OMICHINSKI, J.G., KENNEDY, W.M.P.,
SAKAGUCHI, K., APPELLA, E. AND GRONENBORN, A.M.
Refined solution structure of the oligomerisation domain of the tumour
suppressor p53.
STRUCT.BIOL. 2(4) 321-333 (1995).
2. SOUSSI, T., DEFROMENTEL, C.C. AND MAY, P.
Structural aspects of the P53 protein in relation to gene evolution.
ONCOGENE 5(7) 945-952 (1990).
3. CLORE, G.M., OMICHINSKI, J.G., SAKAGUCHI, K., ZAMBRANO, N., SAKAMOTO, H.,
APPELLA, E. AND GRONENBORN, A.M.
High-resolution structure of the oligomerization domain of P53 by
multidimensional NMR.
SCIENCE 265 346-355 (1996).
|
| Documentation | The tumour suppressor P53 is involved in 50% of all human cancers [1-3].
The protein has been implicated in cell cycle regulation, particularly in
the monitoring of genomic DNA integrity prior to replication; for this
reason it has been dubbed `guardian of the genome'. P53 is a sequence-
specific DNA-binding protein and transcription factor; downstream targets
include the gene for p21, whose product inhibits cyclin-dependent kinase-4,
thereby blocking cell division.
The structure of P53 comprises 4 domains: an N-terminal transactivation
domain; a central DNA-binding domain; an oligomerisation domain; and a
C-terminal, basic, regulatory domain [1,3]. The structure of the oligo-
merisation domain consists of a dimer of dimers, each dimer consisting
of 2 anti-parallel alpha-helices and an anti-parallel beta-sheet. The sheets
lie on opposite sides of the tetramer and the helices form an unusual
4-helix bundle [1,3]. While the majority of P53 mutations found in human
cancers are located in the DNA-binding domain, some are also found in
the oligomerisation domain.
P53SUPPRESSR is a 6-element fingerprint that provides a signature for p53
tumour suppressor proteins. The fingerprint was derived from an initial
alignment of 9 sequences: the motifs were largely drawn from conserved
regions within the central DNA-binding domain - motif 1 spans loop L1, beta-
hairpin S2 S2' and connecting loop; motif 2 spans strand S4, loop L2 and
helix H1, and includes 2 of the zinc ligands (Cys176 and His179); motif 3
spans strands S7 and S8 and the connecting loop; motif 4, which contains the
remaining 2 zinc ligands (Cys238 and Cys242), spans loop L3 and strand S9,
and includes the region encoded by PROSITE pattern P53 (PS00348), which is
involved in binding the large T antigen of SV40 [2]; motif 5 spans strand
S10, helix H2 and the connecting loop; and motif 6 lies within the oligo-
merisation domain. Two iterations on OWL26.0 were required to reach
convergence, at which point a true set comprising 23 sequences was
identified. A single partial match was also found, a fragment lacking
the final 4 motifs.
An update on SPTR37_9f identified a true set of 36 sequences.
|