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Structure and Function of p53-DNA Complexes with Inactivation and Rescue Mutations: A Molecular Dynamics Simulation Study - PubMed

  • ️Thu Jan 01 2015

Structure and Function of p53-DNA Complexes with Inactivation and Rescue Mutations: A Molecular Dynamics Simulation Study

Balu Kamaraj et al. PLoS One. 2015.

Abstract

The tumor suppressor protein p53 can lose its function upon DNA-contact mutations (R273C and R273H) in the core DNA-binding domain. The activity can be restored by second-site suppressor or rescue mutations (R273C_T284R, R273H_T284R, and R273H_S240R). In this paper, we elucidate the structural and functional consequence of p53 proteins upon DNA-contact mutations and rescue mutations and the underlying mechanisms at the atomic level by means of molecular dynamics simulations. Furthermore, we also apply the docking approach to investigate the binding phenomena between the p53 protein and DNA upon DNA-contact mutations and rescue mutations. This study clearly illustrates that, due to DNA-contact mutants, the p53 structure loses its stability and becomes more rigid than the native protein. This structural loss might affect the p53-DNA interaction and leads to inhibition of the cancer suppression. Rescue mutants (R273C_T284R, R273H_T284R and R273H_S240R) can restore the functional activity of the p53 protein upon DNA-contact mutations and show a good interaction between the p53 protein and a DNA molecule, which may lead to reactivate the cancer suppression function. Understanding the effects of p53 cancer and rescue mutations at the molecular level will be helpful for designing drugs for p53 associated cancer diseases. These drugs should be designed so that they can help to inhibit the abnormal function of the p53 protein and to reactivate the p53 function (cell apoptosis) to treat human cancer.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Mechanism of p53-DNA interaction upon DNA-contact and rescue mutations.

(A) Shows the normal p53-DNA interaction, leading to cancer suppression. (B) Illustrates how a DNA-contact mutation results in a reduced p53-DNA affinity, which is a possible cause of cancer. (C) Shows that a rescue mutation can restore the good p53-DNA affinity, and thus give again rise to cancer suppression.

Fig 2
Fig 2. RMSD of native, DNA-contact (R273C and R273H) and rescue mutants (R273C_T284R, R273H_T284R and R273H_S240R) of the p53 protein versus time at 300K.

(a) Native, R273C and R273C_T284R, (b) Native, R273H and R273H_T284R, (c) Native, R273H and R273H_S240R.

Fig 3
Fig 3. RMSF of the backbone of C-alpha atoms of native, DNA-contact (R273C and R273H) and rescue mutants (R273C_T284R, R273H_T284R and R273H_S240R) of the p53 protein versus residue at 300K.

(a) Native, R273C and R273C_T284R, (b) Native, R273H and R273H_T284R, (c) Native, R273H and R273H_S240R.

Fig 4
Fig 4. Radius of gyration of C-alpha atoms of native, DNA-contact (R273C and R273H) and rescue mutants (R273C_T284R, R273H_T284R and R273H_S240R) of the p53 protein versus time at 300K.

(a) Native, R273C and R273C_T284R, (b) Native, R273H and R273H_T284R, (c) Native, R273H and R273H_S240R.

Fig 5
Fig 5. Solvent accessible surface area (SASA) of native, DNA-contact (R273C and R273H) and rescue mutants (R273C_T284R, R273H_T284R and R273H_S240R) of the p53 protein versus time at 300K.

(a) Native, R273C and R273C_T284R, (b) Native, R273H and R273H_T284R, (c) Native, R273H and R273H_S240R.

Fig 6
Fig 6. Average number of intermolecular hydrogen bonds in native, DNA-contact (R273C and R273H) and rescue mutants (R273C_T284R, R273H_T284R and R273H_S240R) of the p53 protein versus time at 300K.

(a) Native, R273C and R273C_T284R, (b) Native, R273H and R273H_T284R, (c) Native, R273H and R273H_S240R.

Fig 7
Fig 7. Projection of the motion of the p53 protein in phase space along the first two principal eigenvectors at 300 K.

(a) Native, R273C and R273C_T284R, (b) Native, R273H and R273H_T284R, (c) Native, R273H and R273H_S240R.

Fig 8
Fig 8. Residue interaction at the protein-DNA interface in the p53-DNA complex.

(a) Native-DNA complex, (b) R273C-DNA complex, (c) R273H-DNA complex, (d) R273C_T284R-DNA complex, (e) R273H_T284R-DNA complex and (f) R273H_S240R-DNA complex. The color coding represents the p53 protein in brown color, DNA in purple color. Hydrogen bonding interactions are denoted by dashed lines. This figure was prepared by Ligplot.

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References

    1. Brown CJ, Lain S, Verma CS, Fersht AR, Lane DP. Awakening guardian angels: drugging the p53 pathway. Nat Rev Cancer 2009;9: 862–873. 10.1038/nrc2763 - DOI - PubMed
    1. Meulmeester E, Jochemsen AG. p53: a guide to apoptosis. Curr Cancer Drug Targets 2008;8: 87–97. - PubMed
    1. Lim YP, Lim TT, Chan YL, Song AC, Yeo BH, Vojtesek B, et al. The p53 knowledgebase: an integrated information resource for p53 research. Oncogene 2007;26: 1517–1521. - PubMed
    1. Gomez-Lazaro M, Fernandez-Gomez FJ, Jordán J. p53: twenty five years understanding the mechanism of genome protection. J PhysiolBiochem 2004;60: 287–307. - PubMed
    1. Sakaguchi K, Sakamoto H, Xie D, Erickson JW, Lewis MS, Anderson CW et al. Effect of phosphorylation on tetramerization of the tumor suppressor protein p53. J Protein Chem. 1997;16: 553–556. - PubMed

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This research was financially supported by the Methusalem funding.