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

Kamaraj B, Bogaerts A - PLoS ONE (2015)

Bottom Line: 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).This study clearly illustrates that, due to DNA-contact mutants, the p53 structure loses its stability and becomes more rigid than the native protein.

View Article: PubMed Central - PubMed

Affiliation: Research group PLASMANT, Department of Chemistry, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk-Antwerp, Belgium.

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.

No MeSH data available.


Related in: MedlinePlus

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.
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pone.0134638.g005: 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.

Mentions: Fig 5 illustrates the change of SASA for the native, DNA-contact (R273C and R273H) and rescue mutants (R273C_T284R, R273H_T284R and R273H_S240R) of the p53 protein with time. SASA is the surface area of the biomolecules that is accessible to the solvent. The average SASA values of the native, DNA-contact and rescue mutants are again listed in S1 Table. The lower fluctuation in Rg plots in both DNA-contact mutant structures indicates that the protein might be undergoing a significant structural transition. This is further supported by the SASA result, where the DNA-contact mutants (R273C and R273H) exhibit lower values of SASA as compared to the native p53 protein. A lower value of SASA in the DNA-contact mutant structures denotes its relatively shrunken nature as compared to the native p53 structure. The rescue mutants, on the other hand, can reach the fluctuation of the native p53 protein at the end of the simulation in both the Rg and SASA plot (Fig 4A–4C and Fig 5A–5C). It indicates that the rescue mutants (R273C_T284R, R273H_T284R and R273H_S240R) can restore the structural changes in the p53 protein upon DNA-contact mutant (R273C and R273H) structures.


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

Kamaraj B, Bogaerts A - PLoS ONE (2015)

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.
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pone.0134638.g005: 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.
Mentions: Fig 5 illustrates the change of SASA for the native, DNA-contact (R273C and R273H) and rescue mutants (R273C_T284R, R273H_T284R and R273H_S240R) of the p53 protein with time. SASA is the surface area of the biomolecules that is accessible to the solvent. The average SASA values of the native, DNA-contact and rescue mutants are again listed in S1 Table. The lower fluctuation in Rg plots in both DNA-contact mutant structures indicates that the protein might be undergoing a significant structural transition. This is further supported by the SASA result, where the DNA-contact mutants (R273C and R273H) exhibit lower values of SASA as compared to the native p53 protein. A lower value of SASA in the DNA-contact mutant structures denotes its relatively shrunken nature as compared to the native p53 structure. The rescue mutants, on the other hand, can reach the fluctuation of the native p53 protein at the end of the simulation in both the Rg and SASA plot (Fig 4A–4C and Fig 5A–5C). It indicates that the rescue mutants (R273C_T284R, R273H_T284R and R273H_S240R) can restore the structural changes in the p53 protein upon DNA-contact mutant (R273C and R273H) structures.

Bottom Line: 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).This study clearly illustrates that, due to DNA-contact mutants, the p53 structure loses its stability and becomes more rigid than the native protein.

View Article: PubMed Central - PubMed

Affiliation: Research group PLASMANT, Department of Chemistry, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk-Antwerp, Belgium.

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.

No MeSH data available.


Related in: MedlinePlus