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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

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.
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pone.0134638.g001: 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.

Mentions: The PDB structures of the p53 coredomain bound to DNA [28–34] show that the guanidinium groups of the R273 residues (positively charged) interact with the DNA backbone (negatively charged) at the center of each DNA half-site, which is supported by hydrogen bonding and salt-bridge interactions. TheR273 residues play an important role in docking, to study the p53 interaction with the DNA backbone [35, 36]. Substitution of R273 by histidine or cysteine amino acid residues, referred to as R273H and R273C, leads to a dramatic reduction in the DNA binding affinity [37]. Inactivation of the resulting mutant p53 function is a tough challenge. Reversing the effect of single mutations (R273H and R273C) in the p53 core domain is rescued by second-site suppressor mutations (T284R, S240R), which leads to a reactivation of the normal p53 activity (i.e., DNA binding, transcriptional activation and tumor-suppressing activity)[34]. Mutant T284R (i.e., substitution of threonine by arginine at position 284) could restore the activity of R273H and R273C mutations [38] whereas mutant S240R (i.e., substitution of serine by arginine at position 240), could rescue the R273H mutation [39]. The overall mechanism of native, DNA-contact mutants and rescue mutants of the p53-DNA complex is shown in Fig 1.


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

Kamaraj B, Bogaerts A - PLoS ONE (2015)

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.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4526489&req=5

pone.0134638.g001: 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.
Mentions: The PDB structures of the p53 coredomain bound to DNA [28–34] show that the guanidinium groups of the R273 residues (positively charged) interact with the DNA backbone (negatively charged) at the center of each DNA half-site, which is supported by hydrogen bonding and salt-bridge interactions. TheR273 residues play an important role in docking, to study the p53 interaction with the DNA backbone [35, 36]. Substitution of R273 by histidine or cysteine amino acid residues, referred to as R273H and R273C, leads to a dramatic reduction in the DNA binding affinity [37]. Inactivation of the resulting mutant p53 function is a tough challenge. Reversing the effect of single mutations (R273H and R273C) in the p53 core domain is rescued by second-site suppressor mutations (T284R, S240R), which leads to a reactivation of the normal p53 activity (i.e., DNA binding, transcriptional activation and tumor-suppressing activity)[34]. Mutant T284R (i.e., substitution of threonine by arginine at position 284) could restore the activity of R273H and R273C mutations [38] whereas mutant S240R (i.e., substitution of serine by arginine at position 240), could rescue the R273H mutation [39]. The overall mechanism of native, DNA-contact mutants and rescue mutants of the p53-DNA complex is shown in Fig 1.

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