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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

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.
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pone.0134638.g007: 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.

Mentions: To further support our results, we performed an essential dynamics (ED) analysis to obtain a better view of the dynamical mechanical property of the investigated structures. In ED analysis, we applied a simple linear transformation in the Cartesian coordinate space and the diagonalization of the covariance matrix. It yields a set of eigenvectors, which gives a vectorial depiction of every single component of the motion indicative of the direction of motion. Within the top eigenvectors, the first two accounted for a significant amount of overall motion in each case. Each eigenvector has a corresponding eigenvalue, which describes the energetic involvement of each component to the motion. The projection of trajectories obtained at 300 K onto the first two principal components (PC1, PC2) shows the motion of native and DNA-contact and rescue mutant p53 proteins in phase space and is illustrated in Fig 7A–7C. In the ED analysis, both DNA-contact mutants (R273C and R273H) cover a smaller region of phase space than the native structure, particularly along the PC2 and PC1 plane, whereas the rescue mutations of R273C (R273C_T284R) and R273H (R273H_T284R and R273H_S240R) show a similar phase space behaviour as the native protein. The overall flexibility of the native structure, and the DNA-contact and rescue mutants was calculated by the trace of the diagonalized covariance matrix of the Cα-atomic positional fluctuations (S1 Table: covariance value). From Fig 7A–7C and S1 Table, it is clear that the overall flexibility was reduced in both DNA-contact (R273C and R273H) mutants compared to the native structure at 300K. Moreover, the rescue mutants can restore the flexibility in the p53 protein upon DNA-contact mutants and show a similar way of motions as the native protein, thus restoring the normal function of the p53 protein upon DNA-contact mutations.


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

Kamaraj B, Bogaerts A - PLoS ONE (2015)

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.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4526489&req=5

pone.0134638.g007: 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.
Mentions: To further support our results, we performed an essential dynamics (ED) analysis to obtain a better view of the dynamical mechanical property of the investigated structures. In ED analysis, we applied a simple linear transformation in the Cartesian coordinate space and the diagonalization of the covariance matrix. It yields a set of eigenvectors, which gives a vectorial depiction of every single component of the motion indicative of the direction of motion. Within the top eigenvectors, the first two accounted for a significant amount of overall motion in each case. Each eigenvector has a corresponding eigenvalue, which describes the energetic involvement of each component to the motion. The projection of trajectories obtained at 300 K onto the first two principal components (PC1, PC2) shows the motion of native and DNA-contact and rescue mutant p53 proteins in phase space and is illustrated in Fig 7A–7C. In the ED analysis, both DNA-contact mutants (R273C and R273H) cover a smaller region of phase space than the native structure, particularly along the PC2 and PC1 plane, whereas the rescue mutations of R273C (R273C_T284R) and R273H (R273H_T284R and R273H_S240R) show a similar phase space behaviour as the native protein. The overall flexibility of the native structure, and the DNA-contact and rescue mutants was calculated by the trace of the diagonalized covariance matrix of the Cα-atomic positional fluctuations (S1 Table: covariance value). From Fig 7A–7C and S1 Table, it is clear that the overall flexibility was reduced in both DNA-contact (R273C and R273H) mutants compared to the native structure at 300K. Moreover, the rescue mutants can restore the flexibility in the p53 protein upon DNA-contact mutants and show a similar way of motions as the native protein, thus restoring the normal function of the p53 protein upon DNA-contact mutations.

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