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Crystal structure of a p53 core tetramer bound to DNA.

Malecka KA, Ho WC, Marmorstein R - Oncogene (2008)

Bottom Line: The structure reveals that two p53DBD dimers bind to B form DNA with no relative twist and that a p53 tetramer can bind to DNA without introducing significant DNA bending.The numerous dimer-dimer interactions involve several strictly conserved residues, thus suggesting a molecular basis for p53DBD-DNA binding cooperativity.Surface residue conservation of the p53DBD tetramer bound to DNA highlights possible regions of other p53 domain or p53 cofactor interactions.

View Article: PubMed Central - PubMed

Affiliation: The Wistar Institute, Philadelphia, PA 19104, USA.

ABSTRACT
The tumor suppressor p53 regulates downstream genes in response to many cellular stresses and is frequently mutated in human cancers. Here, we report the use of a crosslinking strategy to trap a tetrameric p53 DNA-binding domain (p53DBD) bound to DNA and the X-ray crystal structure of the protein/DNA complex. The structure reveals that two p53DBD dimers bind to B form DNA with no relative twist and that a p53 tetramer can bind to DNA without introducing significant DNA bending. The numerous dimer-dimer interactions involve several strictly conserved residues, thus suggesting a molecular basis for p53DBD-DNA binding cooperativity. Surface residue conservation of the p53DBD tetramer bound to DNA highlights possible regions of other p53 domain or p53 cofactor interactions.

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Related in: MedlinePlus

Surface map of amino acid conservation in p53DBD. (a) A sequence alignment was performed with all known sequences of p53 using ClustalW (Gasteiger et al., 2003) and mapped with ESPript (Gouet et al., 1999). View of subunits A and D with strictly conserved residues colored in red to nonconserved residues in blue (DeLano, 2002). The DNA is rendered in gray. Subunits B and C have been removed for clarity. Monomer-dimer interface is circled with a black, dashed line. (b) View along the helical axis of subunits A and B with subunits C and D removed for clarity. Dimer-dimer interface is circled with a black, dashed line. (c) Back view of subunits B and C showing the band of conserved residues that wrap around each subunit.
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Figure 5: Surface map of amino acid conservation in p53DBD. (a) A sequence alignment was performed with all known sequences of p53 using ClustalW (Gasteiger et al., 2003) and mapped with ESPript (Gouet et al., 1999). View of subunits A and D with strictly conserved residues colored in red to nonconserved residues in blue (DeLano, 2002). The DNA is rendered in gray. Subunits B and C have been removed for clarity. Monomer-dimer interface is circled with a black, dashed line. (b) View along the helical axis of subunits A and B with subunits C and D removed for clarity. Dimer-dimer interface is circled with a black, dashed line. (c) Back view of subunits B and C showing the band of conserved residues that wrap around each subunit.

Mentions: A surface conservation map of the p53DBD in the context of the p53DBD tetramer bound to DNA reveals several areas of high conservation and by inference functional importance. The highest degree of conservation maps to the DNA binding region of the monomer and the monomer-dimer interface (Figure 5a) highlighting the relative importance of these regions. In contrast, the dimer-dimer interface shows far less conservation (Figure 5b) arguing for a less significant role of p53DBD dimer-dimer contacts for DNA recognition. Subunit A shows a long groove of conservation that is set back from the L2 loop. A mirrored pattern on subunit B would suggest a strict dimer-dimer interaction, but this is not seen and further supports the model that multiple tetramerization modes can accommodate p53 binding to DNA.


Crystal structure of a p53 core tetramer bound to DNA.

Malecka KA, Ho WC, Marmorstein R - Oncogene (2008)

Surface map of amino acid conservation in p53DBD. (a) A sequence alignment was performed with all known sequences of p53 using ClustalW (Gasteiger et al., 2003) and mapped with ESPript (Gouet et al., 1999). View of subunits A and D with strictly conserved residues colored in red to nonconserved residues in blue (DeLano, 2002). The DNA is rendered in gray. Subunits B and C have been removed for clarity. Monomer-dimer interface is circled with a black, dashed line. (b) View along the helical axis of subunits A and B with subunits C and D removed for clarity. Dimer-dimer interface is circled with a black, dashed line. (c) Back view of subunits B and C showing the band of conserved residues that wrap around each subunit.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2629805&req=5

Figure 5: Surface map of amino acid conservation in p53DBD. (a) A sequence alignment was performed with all known sequences of p53 using ClustalW (Gasteiger et al., 2003) and mapped with ESPript (Gouet et al., 1999). View of subunits A and D with strictly conserved residues colored in red to nonconserved residues in blue (DeLano, 2002). The DNA is rendered in gray. Subunits B and C have been removed for clarity. Monomer-dimer interface is circled with a black, dashed line. (b) View along the helical axis of subunits A and B with subunits C and D removed for clarity. Dimer-dimer interface is circled with a black, dashed line. (c) Back view of subunits B and C showing the band of conserved residues that wrap around each subunit.
Mentions: A surface conservation map of the p53DBD in the context of the p53DBD tetramer bound to DNA reveals several areas of high conservation and by inference functional importance. The highest degree of conservation maps to the DNA binding region of the monomer and the monomer-dimer interface (Figure 5a) highlighting the relative importance of these regions. In contrast, the dimer-dimer interface shows far less conservation (Figure 5b) arguing for a less significant role of p53DBD dimer-dimer contacts for DNA recognition. Subunit A shows a long groove of conservation that is set back from the L2 loop. A mirrored pattern on subunit B would suggest a strict dimer-dimer interaction, but this is not seen and further supports the model that multiple tetramerization modes can accommodate p53 binding to DNA.

Bottom Line: The structure reveals that two p53DBD dimers bind to B form DNA with no relative twist and that a p53 tetramer can bind to DNA without introducing significant DNA bending.The numerous dimer-dimer interactions involve several strictly conserved residues, thus suggesting a molecular basis for p53DBD-DNA binding cooperativity.Surface residue conservation of the p53DBD tetramer bound to DNA highlights possible regions of other p53 domain or p53 cofactor interactions.

View Article: PubMed Central - PubMed

Affiliation: The Wistar Institute, Philadelphia, PA 19104, USA.

ABSTRACT
The tumor suppressor p53 regulates downstream genes in response to many cellular stresses and is frequently mutated in human cancers. Here, we report the use of a crosslinking strategy to trap a tetrameric p53 DNA-binding domain (p53DBD) bound to DNA and the X-ray crystal structure of the protein/DNA complex. The structure reveals that two p53DBD dimers bind to B form DNA with no relative twist and that a p53 tetramer can bind to DNA without introducing significant DNA bending. The numerous dimer-dimer interactions involve several strictly conserved residues, thus suggesting a molecular basis for p53DBD-DNA binding cooperativity. Surface residue conservation of the p53DBD tetramer bound to DNA highlights possible regions of other p53 domain or p53 cofactor interactions.

Show MeSH
Related in: MedlinePlus