Factors governing loss and rescue of DNA binding upon single and double mutations in the p53 core domain

Wright, Jon D.; Noskov, Sergei Y.; Lim, Carmay

doi:10.1093/nar/30.7.1563

Cited by 33 publications

(34 citation statements)

References 50 publications

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“…His residues in the biologically active state should be protonated. We selectively protonated five His residues according to the suggestion of Wright et al (28). The only two His residues left in the deprotonated state are His-179, which is coordinated to Zn, and His-214, which is close to R174.…”

Section: Surface Analysis Of the P53 Cbd: Identification Of Protein-pmentioning

confidence: 99%

Comparison of the protein–protein interfaces in the p53–DNA crystal structures: Towards elucidation of the biological interface

Pan

Gunasekaran

et al. 2005

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

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p53, the tumor suppressor protein, functions as a dimer of dimers. However, how the tetramer binds to the DNA is still an open question. In the crystal structure, three copies of the p53 monomers (containing chains A, B, and C) were crystallized with the DNAconsensus element. Although the structure provides crucial data on the p53-DNA contacts, the active oligomeric state is unclear because the two dimeric (A-B and B-C) interfaces present in the crystal cannot both exist in the tetramer. Here, we address the question of which of these two dimeric interfaces may be more biologically relevant. We analyze the sequence and structural properties of the p53-p53 dimeric interfaces and carry out extensive molecular dynamics simulations of the crystal structures of the human and mouse p53 dimers. We find that the A-B interface residues are more conserved than those of the B-C. Molecular dynamics simulations show that the A-B interface can provide a stable DNA-binding motif in the dimeric state, unlike B-C. Our results indicate that the interface between chains A-B in the p53-DNA complex constitutes a better candidate for a stable biological interface, whereas the B-C interface is more likely to be due to crystal packing. Thus, they have significant implications toward our understanding of DNA binding by p53 as well as p53-mediated interactions with other proteins. p53 dimeric interface ͉ p53 tetramer ͉ hot spots ͉ cancer ͉ gene regulation

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Section: Surface Analysis Of the P53 Cbd: Identification Of Protein-pmentioning

confidence: 99%

Comparison of the protein–protein interfaces in the p53–DNA crystal structures: Towards elucidation of the biological interface

Pan

Gunasekaran

et al. 2005

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

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show abstract

“…Although it was reported that the K120R mutant binds p53 target sites equally well as wt p53, this was only investigated for a limited number of target genes. 151 The K120 residue in p53, however, interacts with the major groove of DNA 170 and, therefore, possible phenotypes arising in putative K120R knock-in mice may not entirely be due to the effects on target gene expression caused by loss of p53 acetylation.…”

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confidence: 99%

How important are post-translational modifications in p53 for selectivity in target-gene transcription and tumour suppression?

et al. 2007

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A number of elegant studies exploring the consequences of expression of various mutant forms of p53 in mice have been published over the last years. The results and conclusions drawn from these studies often contradict results previously obtained in biochemical assays and cell biology studies, questioning their relevance for p53 function in vivo. Owing to the multitude of post-translational modifications imposed on p53, however, the in vivo validation of their relevance for proper protein function and tumour suppression is constantly lagging behind new biochemical discoveries. Nevertheless, mouse genetics presents again its enormous power. Despite being relatively slow and tedious, it has become indispensable for researchers to sort out the wheat from the chaff in an endless sea of publications on p53. Cell Death and Differentiation (2007) 14, 1561-1575; doi:10.1038/sj.cdd.4402196; published online 13 July 2007To this very moment, more than 42 500 papers have been published dealing with p53, in one or the other way, and still we are not quite sure what all of its biological functions are and how exactly it activates and coordinates them. What we assume is that p53 acts predominantly as a transcription factor, regulating the expression of more than 100 target genes to initiate apoptosis, cell cycle arrest, DNA-repair, cellular senescence as well as differentiation. 1 We cannot be entirely certain that transcriptional activation of target genes is the only way by which p53 exerts its biological functions, because it has also been reported to translocate to the outer mitochondrial membrane where it interacts with pro-and antiapoptotic members of the Bcl-2 protein family. 2This review focuses on post-translational modifications, which have been reported to modulate p53's transcriptional activity and their influence on target gene expression, in particular those involved in cell cycle arrest and apoptosis. We have also tried to summarize attempts to verify the most important in vitro findings on p53 modification using knock-in mouse models that express certain variants of the molecule that lack key-residues subjected to post-translational modifications, or, entire portions of the protein considered relevant for proper function. Target Genes Relevant for p53-Mediated Growth Arrest and Cell DeathThe tumour suppressor function of p53 is based on its ability to regulate a range of cellular functions, including cell growth, cell cycle progression, DNA-repair, cellular senescence and cell death. We can assume today that deregulation of all these processes contributes to neoplastic transformation of p53-deficient cells.The ability of p53 to induce cell cycle arrest depends on three critical target genes: p21, 3 14-3-3s 4 and GADD45 (growth arrest and DNA damage-inducible protein 45).5 The transactivation of p21 triggers G1 cell cycle arrest through inhibition of G1 cyclin-dependent kinases (cyclinA/CDK2, cyclinE/CDK2 and cyclinD/CDK4 complexes).6 Maintenance of the Rb-E2F complex and consequent inhibition of S phase entry t...

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“…MD simulations have been performed to study structural and dynamic properties of the p53, DNA binding domain [36][37][38]. Although, only few MD simulations on p53-DNA wild type complex and its mutational effects have been reported till date [36,39,40]. Free energy calculations through MD simulations are reported to identify loss and rescue of DNA binding to p53 core domain by single and double mutations [39,40].…”

Section: Introductionmentioning

confidence: 99%

“…Although, only few MD simulations on p53-DNA wild type complex and its mutational effects have been reported till date [36,39,40]. Free energy calculations through MD simulations are reported to identify loss and rescue of DNA binding to p53 core domain by single and double mutations [39,40]. One of the recent MD simulations on the p53 monomer, depicts a computational metric which helps to determine the functionality of a particular p53 mutant [41].…”

Section: Introductionmentioning

confidence: 99%

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QM-MM simulations on p53-DNA complex: a study of hot spot and rescue mutants

et al. 2013

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p53 is a transcription factor involved in the expression of a number of downstream genes in response to genotoxic stress. It is activated through post translation modifications in normal as well as cancerous cells. However, due to mutations occurring in p53 in cancer cells it is not able to perform its function of DNA binding which leads to cell proliferation. It is found to be mutated in 50% of the cancers. These mutations occur at a high frequency in the DNA binding region of the p53. Among the known seven hot spot cancer mutations G245S, R249S, and R273C have been studied here using quantum mechanics and molecular mechanics (QM-MM) simulations. These mutations along with their experimentally proven rescue mutations have also been included in the present work. A comparative study of these cancer mutations along with wild type and their rescue mutations has been performed. A computational measure based on the free energy changes occurring in the binding of the p53 to the DNA has been presented. A correlation between the DNA binding property and important interaction between p53 and DNA has been observed for all the mutants. The keys residues which contribute to the binding of p53 to DNA by forming crucial hydrogen bonds have also been discussed in detail. A 30 ns simulation study was analyzed to observe the local structural changes and DNA binding property of p53 in case of wild type, cancer and rescue mutants.

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Factors governing loss and rescue of DNA binding upon single and double mutations in the p53 core domain

Cited by 33 publications

References 50 publications

Comparison of the protein–protein interfaces in the p53–DNA crystal structures: Towards elucidation of the biological interface

Comparison of the protein–protein interfaces in the p53–DNA crystal structures: Towards elucidation of the biological interface

How important are post-translational modifications in p53 for selectivity in target-gene transcription and tumour suppression?

QM-MM simulations on p53-DNA complex: a study of hot spot and rescue mutants

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