The effect of mutations on peptide models of the DNA binding helix of p53: Evidence for a correlation between structure and tumorigenesis

Trulson, Julie A.; Millhauser, Glenn L.

doi:10.1002/(sici)1097-0282(199903)49:3<215::aid-bip3>3.0.co;2-f

Cited by 4 publications

(4 citation statements)

References 40 publications

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“…Thus, the calculations suggest a central role for D281 in helping to orient R273 and R280 for hydrogen bonding to the DNA, consistent with the observation that D281 is strictly conserved across 27 species that p53 has been sequenced for (48). Mutation of D281 to Asn or the charge-preserving Glu in p53 has been found in tumour cells, implying that the mutant cannot bind to DNA specifically and function as a tumour suppressor gene.…”

Section: Factors Affecting Loss Of Dna Binding Upon Mutating R273→h I...supporting

confidence: 78%

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

Wright

Noskov²,

Lim³

2002

Nucleic Acids Research

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The mutation of R273-->H in the p53 core domain (p53-CD) is one of the most common mutations found in human cancers. Although the 273H p53-CD retains the wild-type conformation and stability, it lacks sequence-specific DNA binding, a transactivation function and growth suppression. However, mutating T284-->R in the 273H p53-CD restores the DNA binding affinity, and transactivation and tumour suppressor functions. Since X-ray/NMR structures of DNA-free or DNA-bound mutant p53-CD molecules are unavailable, the factors governing the loss and rescue of sequence-specific DNA binding in the 273H and 273H+284R p53-CD, respectively, are unclear. Hence, we have carried out molecular dynamics (MD) simulations of the wild-type, single mutant and double mutant p53-CD, free and DNA bound, in the presence of explicit water molecules. Based on the MD structures, the DNA-binding free energy of each p53 molecule has been computed and decomposed into component energies and contributions from the interface residues. The wild-type and mutant p53-CD MD structures were found to be consistent with the antibody-binding, X-ray and NMR data. The predicted DNA binding affinity and specificity of both mutant p53-CDs were also in accord with experimental data. The non-detectable DNA binding of the 273H p53-CD is due mainly to the disruption of a hydrogen-bonding network involving R273, D281 and R280, leading to a loss of major groove binding by R280 and K120. The restoration of DNA binding affinity and specificity of the 273H+284R p53-CD is due mainly to the introduction of another DNA-binding site at position 284, leading to a recovery of major groove binding by R280 and K120. The important role of water molecules and the DNA major groove conformation as well as implications for structure-based linker rescue of the 273H p53-CD DNA-binding affinity are discussed.

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Section: Factors Affecting Loss Of Dna Binding Upon Mutating R273→h I...supporting

confidence: 78%

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

Wright

Noskov²,

Lim³

2002

Nucleic Acids Research

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“…[39][40][41][42][43][44] Second, partially folded helical peptides serve as templates for exploring helix stabilizing interactions. [45][46][47] For example, the 3K peptide developed by Marqusee and Baldwin forms a stable monomeric helix in aqueous solution. 21 This peptide and similar Ala-rich sequences have been the subject of numerous spectroscopic studies.…”

Section: CD Nmr and Esr Of Helical Peptidesmentioning

confidence: 99%

“…The study of helical peptides offers two unique contributions to the field of protein folding. First, because helix formation during protein folding is often rapid and within the deadtime of time-resolved techniques, partially folded peptides corresponding to native helical sequences provide insight into local folding initiation sites. − Second, partially folded helical peptides serve as templates for exploring helix stabilizing interactions. − For example, the 3K peptide developed by Marqusee and Baldwin forms a stable monomeric helix in aqueous solution This peptide and similar Ala-rich sequences have been the subject of numerous spectroscopic studies.…”

Section: CD Nmr and Esr Of Helical Peptidesmentioning

confidence: 99%

α and 3₁₀: The Split Personality of Polypeptide Helices

1999

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“…The majority of p53 mutations found in human cancer map to the DNA‐binding surface of the p53 protein, comprising 2 large loops, L2 (residues 163–195) and L3 (residues 236–251) and a loop‐sheet‐helix motif (Cho et al, 1994). Some of these mutations affect residues that directly contact the DNA (contact mutations), whereas others not directly involved in DNA binding (structural mutations) are deleterious for p53 function by inducing local unfolding of the protein (Trulson and Millhauser, 1998).…”

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confidence: 99%

p53 mutational spectra are different between squamous-cell carcinomas of the lip and the oral cavity

et al. 2000

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We studied the p53 mutational spectra of 34 lip and 60 intra‐oral squamous‐cell carcinomas and examined possible etiological and prognostic correlations for these tumor sites. For the p53 analysis of exons 5–8, we used PCR/TGGE screening followed by DNA sequencing. Mutations were found in 18/34 (53%) lip and 22/60 (38%) intra‐oral carcinomas. The p53 mutational spectrum of the intra‐oral carcinomas comprised transitions and transversions in nearly equal frequency (11 to 10). In comparison, transitions were 3.5 times more frequent than transversions (14 to 4) in carcinomas of the lip. The predominant types of base change found in intra‐oral tumors were G:C‐to‐T:A transversions and G:C‐to‐A:T transitions (32% each), while in lip tumors G:C‐to‐A:T transitions (70%) were the most frequent. The rate of lip tumors with mutations was higher in non‐smokers (8/13) than in smokers (9/20). In contrast, p53 mutations in intra‐oral tumors clustered in smokers (18/47 vs. 2/10). G:C‐to‐T:A transversions, regarded as tobacco smoke–associated in lung cancer, were found in 2 moderate and 4 heavy smokers with intra‐oral cancer. This base substitution was found in none of our lip cancers. In lip tumors, a high rate of mutations occurred at dipyridine sites (13/18); among these were 8 C‐to‐T transitions and 1 CC‐to‐TT tandem base transition. These changes are characteristic of DNA damage caused by UV light. The presence of mutational events at the DNA‐binding surface of the p53 protein may correlate with poor clinical outcome. However, we could not find any statistically significant correlations between p53 status and survival. Only the recurrence‐free interval was significantly shortened in cases with mutations affecting residues of the DNA‐binding surface of the p53 protein. Int. J. Cancer 88:82–86, 2000. © 2000 Wiley‐Liss, Inc.

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The effect of mutations on peptide models of the DNA binding helix of p53: Evidence for a correlation between structure and tumorigenesis

Cited by 4 publications

References 40 publications

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

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

α and 3₁₀: The Split Personality of Polypeptide Helices

p53 mutational spectra are different between squamous-cell carcinomas of the lip and the oral cavity

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The effect of mutations on peptide models of the DNA binding helix of p53: Evidence for a correlation between structure and tumorigenesis

Cited by 4 publications

References 40 publications

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

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

α and 310: The Split Personality of Polypeptide Helices

p53 mutational spectra are different between squamous-cell carcinomas of the lip and the oral cavity

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α and 3₁₀: The Split Personality of Polypeptide Helices