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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

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.
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pone.0134638.g002: 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.

Mentions: The MD simulations allow us to understand the structural and functional behaviour of the p53 protein upon DNA-contact (R273C and R273H) and their rescue mutations (R273C_T284R, R273H_T284R and R273H_S240R). We studied the RMSD, RMSF, Rg, SASA, and the number of hydrogen bonds (NH-bonds). We also performed ED analysis and cluster analysis, and made a comparison between the native and DNA-contact (R273C and R273H) and rescue mutations (R273C_T284R, R273H_T284R and R273H_S240R) of the p53 protein. The RMSD for all Cα-atoms from the starting structure was analyzed to study the convergence of the protein system. In the RMSD plot, the native and R273C mutant structure show a similar way of deviation from the start till ~ 8000 ps, after which the mutant (R273C) structure shows a decrease in RMSD value in comparison to the native structure till the end of the simulation. The rescue mutation (T284R) of the R273C mutant structure shows a similar way of deviation as the native structure from the start to ~ 6500 ps, but then it shows the same way of deviation as the DNA-contact mutant (R273C), till 85,000ps, after which it rises and becomes similar to the native structure at the timescale of ~95,000 ps, as illustrated in Fig 2A. The average RMSD value of the native, DNA-contact mutant R273C and its rescue mutant (R273C_T284R) are presented in S1 Table. In Fig 2B and 2C, the native and mutant R273H show a similar way of deviation from the start till ~21,000 ps. Subsequently, the mutant (R273H) structure shows a smaller deviation till the end of the simulations, while the rescue mutation (T284R) of the R273H mutant and the native structure show the same extent of deviation from the start till ~27,000 ps and again from ~ 41,000 ps to the end of the simulations. Another rescue mutation (S240R) of the R273H mutant structure shows less deviation than the native structure from the start to ~83,000 ps, but afterwards, it shows the same deviations to the end of the simulation (see Fig 2C). The average RMSD values of the DNA-contact mutant R273H and its rescue mutants (R273H_T284R and R273H_S240R) are also presented in S1 Table. This Table indicates that, due to the DNA-contact mutants (R273C and R273H), p53 loses its stability and this affects the structural orientation of the p53 protein, whereas the rescue mutants(R273C_T284R, R273H_T284R and R273H_S240R) restore to some extent the stability of the p53 protein upon DNA-contact mutation (R273C and R273H). This, in turn, leads to reactivate the function of the p53 protein.


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

Kamaraj B, Bogaerts A - PLoS ONE (2015)

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.
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pone.0134638.g002: 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.
Mentions: The MD simulations allow us to understand the structural and functional behaviour of the p53 protein upon DNA-contact (R273C and R273H) and their rescue mutations (R273C_T284R, R273H_T284R and R273H_S240R). We studied the RMSD, RMSF, Rg, SASA, and the number of hydrogen bonds (NH-bonds). We also performed ED analysis and cluster analysis, and made a comparison between the native and DNA-contact (R273C and R273H) and rescue mutations (R273C_T284R, R273H_T284R and R273H_S240R) of the p53 protein. The RMSD for all Cα-atoms from the starting structure was analyzed to study the convergence of the protein system. In the RMSD plot, the native and R273C mutant structure show a similar way of deviation from the start till ~ 8000 ps, after which the mutant (R273C) structure shows a decrease in RMSD value in comparison to the native structure till the end of the simulation. The rescue mutation (T284R) of the R273C mutant structure shows a similar way of deviation as the native structure from the start to ~ 6500 ps, but then it shows the same way of deviation as the DNA-contact mutant (R273C), till 85,000ps, after which it rises and becomes similar to the native structure at the timescale of ~95,000 ps, as illustrated in Fig 2A. The average RMSD value of the native, DNA-contact mutant R273C and its rescue mutant (R273C_T284R) are presented in S1 Table. In Fig 2B and 2C, the native and mutant R273H show a similar way of deviation from the start till ~21,000 ps. Subsequently, the mutant (R273H) structure shows a smaller deviation till the end of the simulations, while the rescue mutation (T284R) of the R273H mutant and the native structure show the same extent of deviation from the start till ~27,000 ps and again from ~ 41,000 ps to the end of the simulations. Another rescue mutation (S240R) of the R273H mutant structure shows less deviation than the native structure from the start to ~83,000 ps, but afterwards, it shows the same deviations to the end of the simulation (see Fig 2C). The average RMSD values of the DNA-contact mutant R273H and its rescue mutants (R273H_T284R and R273H_S240R) are also presented in S1 Table. This Table indicates that, due to the DNA-contact mutants (R273C and R273H), p53 loses its stability and this affects the structural orientation of the p53 protein, whereas the rescue mutants(R273C_T284R, R273H_T284R and R273H_S240R) restore to some extent the stability of the p53 protein upon DNA-contact mutation (R273C and R273H). This, in turn, leads to reactivate the function of the p53 protein.

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