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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

p53DBD dimer-dimer formation. (a) View of subunits A (blue) and D (magenta) in surface representation for structure 1 (DeLano, 2002). Subunits B and C have been removed for clarity. (b) Overall view (left) and close up view (right) of the dimer-dimer interaction between subunits A and D for Structure 1. (c) Overall view (left) and close up view (right) of the dimer-dimer interaction between subunits A and D for structure 2. Hydrogen bonds are depicted as orange dashed lines. The same interactions are seen between subunits B and C for both structures.
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Figure 3: p53DBD dimer-dimer formation. (a) View of subunits A (blue) and D (magenta) in surface representation for structure 1 (DeLano, 2002). Subunits B and C have been removed for clarity. (b) Overall view (left) and close up view (right) of the dimer-dimer interaction between subunits A and D for Structure 1. (c) Overall view (left) and close up view (right) of the dimer-dimer interaction between subunits A and D for structure 2. Hydrogen bonds are depicted as orange dashed lines. The same interactions are seen between subunits B and C for both structures.

Mentions: The DNA contacts made by each subunit to the DNA are essentially as reported by Cho et al.(Cho et al., 1994). Three minor variations, which are also observed in the other p53DBD/DNA structures, are seen in each subunit. First, Lys117 (Lys120 in human p53) of the L1 loop has moved away from the DNA and towards the tetramerization interface as previously described in subunits B and D of structure 1 and all subunits of structure 2 (Figures 1e, 3b, and 3c). In subunits A and C of structure 1, this residue is disordered. Second, Arg280 (Arg283 in human p53), part of the H2 helix, is too far to contact the phosphate backbone. Third, Arg245 (Arg248 in human p53), the most frequently mutated residue in human cancers, adopts two different conformations in structure 1 and its DNA contact changes accordingly. In structure 2 and subunits A and C of structure 1, Arg245 sits in the minor groove and contacts the DNA as reported in Cho et al. However, in subunits B and D of structure 1, the same residue adopts a 90° bend and only contacts the backbone of one DNA strand. Taken together, analysis of the protein/DNA contacts within the tetrameric p53DBD bound to DNA reveals that the basic residues 117, 245 and 280 have variable roles in DNA recognition.


Crystal structure of a p53 core tetramer bound to DNA.

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

p53DBD dimer-dimer formation. (a) View of subunits A (blue) and D (magenta) in surface representation for structure 1 (DeLano, 2002). Subunits B and C have been removed for clarity. (b) Overall view (left) and close up view (right) of the dimer-dimer interaction between subunits A and D for Structure 1. (c) Overall view (left) and close up view (right) of the dimer-dimer interaction between subunits A and D for structure 2. Hydrogen bonds are depicted as orange dashed lines. The same interactions are seen between subunits B and C for both structures.
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Related In: Results  -  Collection

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Figure 3: p53DBD dimer-dimer formation. (a) View of subunits A (blue) and D (magenta) in surface representation for structure 1 (DeLano, 2002). Subunits B and C have been removed for clarity. (b) Overall view (left) and close up view (right) of the dimer-dimer interaction between subunits A and D for Structure 1. (c) Overall view (left) and close up view (right) of the dimer-dimer interaction between subunits A and D for structure 2. Hydrogen bonds are depicted as orange dashed lines. The same interactions are seen between subunits B and C for both structures.
Mentions: The DNA contacts made by each subunit to the DNA are essentially as reported by Cho et al.(Cho et al., 1994). Three minor variations, which are also observed in the other p53DBD/DNA structures, are seen in each subunit. First, Lys117 (Lys120 in human p53) of the L1 loop has moved away from the DNA and towards the tetramerization interface as previously described in subunits B and D of structure 1 and all subunits of structure 2 (Figures 1e, 3b, and 3c). In subunits A and C of structure 1, this residue is disordered. Second, Arg280 (Arg283 in human p53), part of the H2 helix, is too far to contact the phosphate backbone. Third, Arg245 (Arg248 in human p53), the most frequently mutated residue in human cancers, adopts two different conformations in structure 1 and its DNA contact changes accordingly. In structure 2 and subunits A and C of structure 1, Arg245 sits in the minor groove and contacts the DNA as reported in Cho et al. However, in subunits B and D of structure 1, the same residue adopts a 90° bend and only contacts the backbone of one DNA strand. Taken together, analysis of the protein/DNA contacts within the tetrameric p53DBD bound to DNA reveals that the basic residues 117, 245 and 280 have variable roles in DNA recognition.

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