Structure of the p53 Core Domain Dimer Bound to DNA

Ho, William C.; Fitzgerald, Mary X.; Marmorstein, Ronen

doi:10.1074/jbc.m603634200

Cited by 131 publications

(180 citation statements)

References 42 publications

Supporting

Mentioning

155

Contrasting

Unclassified

Order By: Relevance

“…Studies of the structural properties could present significant difficulties for structural biologists. However, with the accumulating experimental structural results 19,20,49 and with more advanced computational power, computational studies can play a more important role in revealing the relationship between the complex structure and transcriptional selection and activity.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

p53-Induced DNA Bending: The Interplay between p53−DNA and p53−p53 Interactions

Pan

Nussinov

2008

J. Phys. Chem. B

View full text Add to dashboard Cite

Specific p53 binding-induced DNA bending and its underlying driving forces are crucial for the understanding of selective transcription activation. Diverse p53-response elements exist in the genome. However, it is not known what determines the DNA bending and to what extent. In order to gain knowledge of the forces that govern the DNA bending, molecular dynamics simulations were performed on a series of p53 core domain tetramer-DNA complexes in which each p53 core domain was bound to a DNA quarter site specifically. By varying the sequence of the central 4-base pairs of each half site, different DNA bending extents were observed. Our analysis shows that the interactions between p53 dimer-dimer were similar in all complexes; on the other hand, specific interactions between the p53 and DNA, including the interactions of Arg280, Lys120 and Arg248 with the DNA varied more significantly. In particular, the Arg280 interactions were better maintained in the complex with the CATG-containing DNA sequence, and were mostly lost in the complex with the CTAG-containing DNA sequence. Structural analysis shows that the base pairings for the CATG sequence were stable throughout the simulation trajectory while those for the CTAG sequence was partially dissociated in part of the trajectory, which affected the stability of nearby Arg280-Gua base interactions. Thus, DNA bending depends on the balance between the p53 dimer-dimer interactions and p53-DNA interactions, which in turn are related to the DNA sequence and DNA flexibility.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Several structures involving p53 core domain-DNA specific binding became available during the last decade 11,[18][19][20] . Biophysical and biochemical data 11,[21][22][23][24] were obtained and a similar p53 core domain tetramer-DNA complex model was proposed 11,[21][22][23][24] .…”

Section: Introductionmentioning

confidence: 99%

p53-Induced DNA Bending: The Interplay between p53−DNA and p53−p53 Interactions

Pan

Nussinov

2008

J. Phys. Chem. B

View full text Add to dashboard Cite

show abstract

“…Most p53 cancer mutations are located in the DNA-binding core domain of the protein (3). This domain has been structurally characterized in complex with its cognate DNA by x-ray crystallography (5,10,11) and in its free form in solution by NMR (12). It consists of a central ␤-sandwich that serves as a basic scaffold for the DNA-binding surface.…”

mentioning

confidence: 99%

Structural basis for understanding oncogenic p53 mutations and designing rescue drugs

Joerger

Ang

Fersht³

2006

Proc. Natl. Acad. Sci. U.S.A.

279

319

View full text Add to dashboard Cite

The DNA-binding domain of the tumor suppressor p53 is inactivated by mutation in Ϸ50% of human cancers. We have solved high-resolution crystal structures of several oncogenic mutants to investigate the structural basis of inactivation and provide information for designing drugs that may rescue inactivated mutants. We found a variety of structural consequences upon mutation: (i) the removal of an essential contact with DNA, (ii) creation of large, water-accessible crevices or hydrophobic internal cavities with no other structural changes but with a large loss of thermodynamic stability, (iii) distortion of the DNA-binding surface, and (iv) alterations to surfaces not directly involved in DNA binding but involved in domain-domain interactions on binding as a tetramer. These findings explain differences in functional properties and associated phenotypes (e.g., temperature sensitivity). Some mutants have the potential of being rescued by a generic stabilizing drug. In addition, a mutation-induced crevice is a potential target site for a mutant-selective stabilizing drug.cancer ͉ crystal ͉ structure ͉ drug design ͉ polymorphism T he tumor suppressor protein p53 is a 393-aa transcription factor that regulates the cell cycle and plays a key role in the prevention of cancer development. In response to oncogenic and other stresses, p53 induces the transcription of a number of target genes, resulting in cell-cycle arrest, senescence, or apoptosis (1, 2). In Ϸ50% of human cancers, p53 is inactivated as a result of missense mutation in the p53 gene (3, 4).The multifunctionality of p53 is reflected in the complexity of its structure. Each chain in the p53 tetramer is composed of several domains. There are well defined DNA-binding and tetramerization domains and highly mobile, largely unstructured regions (5-9). Most p53 cancer mutations are located in the DNA-binding core domain of the protein (3). This domain has been structurally characterized in complex with its cognate DNA by x-ray crystallography (5, 10, 11) and in its free form in solution by NMR (12). It consists of a central ␤-sandwich that serves as a basic scaffold for the DNA-binding surface. The DNA-binding surface is composed of two large loops (L2 and L3) that are stabilized by a zinc ion and a loop-sheet-helix motif. Together, these structural elements form an extended surface that makes specific contacts with the various p53 response elements. The six amino acid residues that are most frequently mutated in human cancer are located in or close to the DNA-binding surface (compare release R10 of the TP53 mutation database at www-p53.iarc.fr) (3). These residues have been classified as ''contact'' (Arg-248 and Arg-273) or ''structural'' (Arg-175, Gly-245, Arg-249, and Arg-282) residues, depending on whether they directly contact DNA or play a role in maintaining the structural integrity of the DNA-binding surface (Fig. 1) (5).Urea denaturation studies have shown that the contact mutation R273H has no effect on the thermodynamic stability of the core domain, wher...

show abstract

“…The DNAbinding core domain (residues 94-294) binds to sequencespecific response elements associated with p53 target gene promoters (12)(13)(14). The structures of the core domain complexes with DNA have been solved by crystallography (15)(16)(17), and in solution in the absence of DNA by NMR (18). The structure of the tetramerization domain has been solved by both NMR and x-ray crystallography (19-21).…”

mentioning

confidence: 99%

Quaternary structures of tumor suppressor p53 and a specific p53–DNA complex

Tidow

Melero

Mylonas

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

183

193

View full text Add to dashboard Cite

The homotetrameric tumor suppressor p53 consists of folded core and tetramerization domains, linked and flanked by intrinsically disordered segments that impede structure analysis by x-ray crystallography and NMR. Here, we solved the quaternary structure of human p53 in solution by a combination of small-angle x-ray scattering, which defined its shape, and NMR, which identified the core domain interfaces and showed that the folded domains had the same structure in the intact protein as in fragments. We combined the solution data with electron microscopy on immobilized samples that provided medium resolution 3D maps. Ab initio and rigid body modeling of scattering data revealed an elongated cross-shaped structure with a pair of loosely coupled core domain dimers at the ends, which are accessible for binding to DNA and partner proteins. The core domains in that open conformation closed around a specific DNA response element to form a compact complex whose structure was independently determined by electron microscopy. The structure of the DNA complex is consistent with that of the complex of four separate core domains and response element fragments solved by x-ray crystallography and contacts identified by NMR. Electron microscopy on the conformationally mobile, unbound p53 selected a minor compact conformation, which resembled the closed conformation, from the ensemble of predominantly open conformations. A multipronged structural approach could be generally useful for the structural characterization of the rapidly growing number of multidomain proteins with intrinsically disordered regions.DNA binding ͉ intrinsically unfolded ͉ modular ͉ natively disordered ͉ protein T he tumor suppressor p53 is a tetrameric, multidomain transcription factor that plays a central role in the cell cycle and maintaining genomic integrity (1, 2). It binds to specific DNA response elements, is integrated in various signaling networks by a multitude of protein-protein interactions, and is controlled by extensive posttranslational modifications (1, 3, 4). p53 protein is a homotetramer of 4 ϫ 393 residues. Each chain consists of two folded domains [the core, and the tetramerization domain (323-360)] that are linked by an intrinsically disordered sequence. The transactivation domain (1-67) (5), proline-rich region (67-94), nuclear localization signal (NLS)-containing region (303-323) (6), and C-terminal negative regulatory domain (360-393) are also intrinsically disordered (7-9) (see refs. 10 and 11 for reviews). The DNAbinding core domain (residues 94-294) binds to sequencespecific response elements associated with p53 target gene promoters (12)(13)(14). The structures of the core domain complexes with DNA have been solved by crystallography (15)(16)(17), and in solution in the absence of DNA by NMR (18). The structure of the tetramerization domain has been solved by both NMR and x-ray crystallography (19-21).Structural studies on full-length p53 have been impeded both by its intrinsic instability and the presence of disordered regions (...

show abstract

Structure of the p53 Core Domain Dimer Bound to DNA

Cited by 131 publications

References 42 publications

p53-Induced DNA Bending: The Interplay between p53−DNA and p53−p53 Interactions

p53-Induced DNA Bending: The Interplay between p53−DNA and p53−p53 Interactions

Structural basis for understanding oncogenic p53 mutations and designing rescue drugs

Quaternary structures of tumor suppressor p53 and a specific p53–DNA complex

Contact Info

Product

Resources

About