ESR spectroscopy identifies inhibitory Cu2+ sites in a DNA-modifying enzyme to reveal determinants of catalytic specificity
The relationship between DNA sequence recognition and catalytic specificity in a DNA-modifying enzyme was explored using paramagnetic Cu2+ ions as probes for ESR spectroscopic and biochemical studies. Electron spin echo envelope modulation spectroscopy establishes that Cu2+ coordinates to histidine...
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| Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 109; no. 17; pp. E993 - E1000 |
|---|---|
| Main Authors | , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
National Academy of Sciences
24.04.2012
National Acad Sciences |
| Series | PNAS Plus |
| Subjects | |
| Online Access | Get full text |
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| Abstract | The relationship between DNA sequence recognition and catalytic specificity in a DNA-modifying enzyme was explored using paramagnetic Cu2+ ions as probes for ESR spectroscopic and biochemical studies. Electron spin echo envelope modulation spectroscopy establishes that Cu2+ coordinates to histidine residues in the EcoRI endonuclease homodimer bound to its specific DNA recognition site. The coordinated His residues were identified by a unique use of Cu2+-ion based long-range distance constraints. Double electron-electron resonance data yield Cu2+-Cu2+ and Cu2+-nitroxide distances that are uniquely consistent with one Cu2+ bound to His114 in each subunit. Isothermal titration calorimetry confirms that two Cu2+ ions bind per complex. Unexpectedly, Mg2+-catalyzed DNA cleavage by EcoRI is profoundly inhibited by Cu2+ binding at these hitherto unknown sites, 13 Å away from the Mg2+ positions in the catalytic centers. Molecular dynamics simulations suggest a model for inhibition of catalysis, whereby the Cu2+ ions alter critical protein-DNA interactions and water molecule positions in the catalytic sites. In the absence of Cu2+, the Mg2+-dependence of EcoRI catalysis shows positive cooperativity, which would enhance EcoRI inactivation of foreign DNA by irreparable double-strand cuts, in preference to readily repaired single-strand nicks. Nonlinear Poisson-Boltzmann calculations suggest that this cooperativity arises because the binding of Mg2+ in one catalytic site makes the surface electrostatic potential in the distal catalytic site more negative, thus enhancing binding of the second Mg2+. Taken together, our results shed light on the structural and electrostatic factors that affect site-specific catalysis by this class of endonucleases. |
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| AbstractList | The relationship between DNA sequence recognition and catalytic specificity in a DNA-modifying enzyme was explored using paramagnetic Cu2+ ions as probes for ESR spectroscopic and biochemical studies. Electron spin echo envelope modulation spectroscopy establishes that Cu2+ coordinates to histidine residues in the EcoRI endonuclease homodimer bound to its specific DNA recognition site. The coordinated His residues were identified by a unique use of Cu2+-ion based long-range distance constraints. Double electron-electron resonance data yield Cu2+-Cu2+ and Cu2+-nitroxide distances that are uniquely consistent with one Cu2+ bound to His114 in each subunit. Isothermal titration calorimetry confirms that two Cu2+ ions bind per complex. Unexpectedly, Mg2+-catalyzed DNA cleavage by EcoRI is profoundly inhibited by Cu2+ binding at these hitherto unknown sites, 13 Aa away from the Mg2+ positions in the catalytic centers. Molecular dynamics simulations suggest a model for inhibition of catalysis, whereby the Cu2+ ions alter critical protein-DNA interactions and water molecule positions in the catalytic sites. In the absence of Cu2+, the Mg2+-dependence of EcoRI catalysis shows positive cooperativity, which would enhance EcoRI inactivation of foreign DNA by irreparable double-strand cuts, in preference to readily repaired single-strand nicks. Nonlinear Poisson-Boltzmann calculations suggest that this cooperativity arises because the binding of Mg2+ in one catalytic site makes the surface electrostatic potential in the distal catalytic site more negative, thus enhancing binding of the second Mg2+. Taken together, our results shed light on the structural and electrostatic factors that affect site-specific catalysis by this class of endonucleases. The relationship between DNA sequence recognition and catalytic specificity in a DNA-modifying enzyme was explored using paramagnetic Cu2+ ions as probes for ESR spectroscopic and biochemical studies. Electron spin echo envelope modulation spectroscopy establishes that Cu2+ coordinates to histidine residues in the EcoRI endonuclease homodimer bound to its specific DNA recognition site. The coordinated His residues were identified by a unique use of Cu2+-ion based long-range distance constraints. Double electron-electron resonance data yield Cu2+-Cu2+ and Cu2+-nitroxide distances that are uniquely consistent with one Cu2+ bound to His114 in each subunit. Isothermal titration calorimetry confirms that two Cu2+ ions bind per complex. Unexpectedly, Mg2+-catalyzed DNA cleavage by EcoRI is profoundly inhibited by Cu2+ binding at these hitherto unknown sites, 13 Å away from the Mg2+ positions in the catalytic centers. Molecular dynamics simulations suggest a model for inhibition of catalysis, whereby the Cu2+ ions alter critical protein-DNA interactions and water molecule positions in the catalytic sites. In the absence of Cu2+, the Mg2+-dependence of EcoRI catalysis shows positive cooperativity, which would enhance EcoRI inactivation of foreign DNA by irreparable double-strand cuts, in preference to readily repaired single-strand nicks. Nonlinear Poisson-Boltzmann calculations suggest that this cooperativity arises because the binding of Mg2+ in one catalytic site makes the surface electrostatic potential in the distal catalytic site more negative, thus enhancing binding of the second Mg2+. Taken together, our results shed light on the structural and electrostatic factors that affect site-specific catalysis by this class of endonucleases. The relationship between DNA sequence recognition and catalytic specificity in a DNA-modifying enzyme was explored using paramagnetic Cu(2+) ions as probes for ESR spectroscopic and biochemical studies. Electron spin echo envelope modulation spectroscopy establishes that Cu(2+) coordinates to histidine residues in the EcoRI endonuclease homodimer bound to its specific DNA recognition site. The coordinated His residues were identified by a unique use of Cu(2+)-ion based long-range distance constraints. Double electron-electron resonance data yield Cu(2+)-Cu(2+) and Cu(2+)-nitroxide distances that are uniquely consistent with one Cu(2+) bound to His114 in each subunit. Isothermal titration calorimetry confirms that two Cu(2+) ions bind per complex. Unexpectedly, Mg(2+)-catalyzed DNA cleavage by EcoRI is profoundly inhibited by Cu(2+) binding at these hitherto unknown sites, 13 Å away from the Mg(2+) positions in the catalytic centers. Molecular dynamics simulations suggest a model for inhibition of catalysis, whereby the Cu(2+) ions alter critical protein-DNA interactions and water molecule positions in the catalytic sites. In the absence of Cu(2+), the Mg(2+)-dependence of EcoRI catalysis shows positive cooperativity, which would enhance EcoRI inactivation of foreign DNA by irreparable double-strand cuts, in preference to readily repaired single-strand nicks. Nonlinear Poisson-Boltzmann calculations suggest that this cooperativity arises because the binding of Mg(2+) in one catalytic site makes the surface electrostatic potential in the distal catalytic site more negative, thus enhancing binding of the second Mg(2+). Taken together, our results shed light on the structural and electrostatic factors that affect site-specific catalysis by this class of endonucleases.The relationship between DNA sequence recognition and catalytic specificity in a DNA-modifying enzyme was explored using paramagnetic Cu(2+) ions as probes for ESR spectroscopic and biochemical studies. Electron spin echo envelope modulation spectroscopy establishes that Cu(2+) coordinates to histidine residues in the EcoRI endonuclease homodimer bound to its specific DNA recognition site. The coordinated His residues were identified by a unique use of Cu(2+)-ion based long-range distance constraints. Double electron-electron resonance data yield Cu(2+)-Cu(2+) and Cu(2+)-nitroxide distances that are uniquely consistent with one Cu(2+) bound to His114 in each subunit. Isothermal titration calorimetry confirms that two Cu(2+) ions bind per complex. Unexpectedly, Mg(2+)-catalyzed DNA cleavage by EcoRI is profoundly inhibited by Cu(2+) binding at these hitherto unknown sites, 13 Å away from the Mg(2+) positions in the catalytic centers. Molecular dynamics simulations suggest a model for inhibition of catalysis, whereby the Cu(2+) ions alter critical protein-DNA interactions and water molecule positions in the catalytic sites. In the absence of Cu(2+), the Mg(2+)-dependence of EcoRI catalysis shows positive cooperativity, which would enhance EcoRI inactivation of foreign DNA by irreparable double-strand cuts, in preference to readily repaired single-strand nicks. Nonlinear Poisson-Boltzmann calculations suggest that this cooperativity arises because the binding of Mg(2+) in one catalytic site makes the surface electrostatic potential in the distal catalytic site more negative, thus enhancing binding of the second Mg(2+). Taken together, our results shed light on the structural and electrostatic factors that affect site-specific catalysis by this class of endonucleases. The relationship between DNA sequence recognition and catalytic specificity in a DNA-modifying enzyme was explored using paramagnetic Cu 2+ ions as probes for ESR spectroscopic and biochemical studies. Electron spin echo envelope modulation spectroscopy establishes that Cu 2+ coordinates to histidine residues in the EcoRI endonuclease homodimer bound to its specific DNA recognition site. The coordinated His residues were identified by a unique use of Cu 2+ -ion based long-range distance constraints. Double electron-electron resonance data yield Cu 2+ -Cu 2+ and Cu 2+ -nitroxide distances that are uniquely consistent with one Cu 2+ bound to His114 in each subunit. Isothermal titration calorimetry confirms that two Cu 2+ ions bind per complex. Unexpectedly, Mg 2+ -catalyzed DNA cleavage by EcoRI is profoundly inhibited by Cu 2+ binding at these hitherto unknown sites, 13 Å away from the Mg 2+ positions in the catalytic centers. Molecular dynamics simulations suggest a model for inhibition of catalysis, whereby the Cu 2+ ions alter critical protein-DNA interactions and water molecule positions in the catalytic sites. In the absence of Cu 2+ , the Mg 2+ -dependence of EcoRI catalysis shows positive cooperativity, which would enhance EcoRI inactivation of foreign DNA by irreparable double-strand cuts, in preference to readily repaired single-strand nicks. Nonlinear Poisson-Boltzmann calculations suggest that this cooperativity arises because the binding of Mg 2+ in one catalytic site makes the surface electrostatic potential in the distal catalytic site more negative, thus enhancing binding of the second Mg 2+ . Taken together, our results shed light on the structural and electrostatic factors that affect site-specific catalysis by this class of endonucleases. The relationship between DNA sequence recognition and catalytic specificity in a DNA-modifying enzyme was explored using paramagnetic Cu2+ ions as probes for ESR spectroscopic and biochemical studies. Electron spin echo envelope modulation spectroscopy establishes that Cu2+ coordinates to histidine residues in the EcoRI endonuclease homodimer bound to its specific DNA recognition site. The coordinated His residues were identified by a unique use of Cu2+-ion based long-range distance constraints. Double electron-electron resonance data yield Cu2+-Cu2+ and Cu2+-nitroxide distances that are uniquely consistent with one Cu2+ bound to His114 in each subunit. Isothermal titration calorimetry confirms that two Cu2+ ions bind per complex. Unexpectedly, Mg2+-catalyzed DNA cleavage by EcoRI is profoundly inhibited by Cu2+ binding at these hitherto unknown sites, 13 Å away from the Mg2+ positions in the catalytic centers. Molecular dynamics simulations suggest a model for inhibition of catalysis, whereby the Cu2+ ions alter critical protein-DNA interactions and water molecule positions in the catalytic sites. In the absence of Cu2+, the Mg2+-dependence of EcoRI catalysis shows positive cooperativity, which would enhance EcoRI inactivation of foreign DNA by irreparable double-strand cuts, in preference to readily repaired single-strand nicks. Nonlinear Poisson-Boltzmann calculations suggest that this cooperativity arises because the binding of Mg2+ in one catalytic site makes the surface electrostatic potential in the distal catalytic site more negative, thus enhancing binding of the second Mg2+. Taken together, our results shed light on the structural and electrostatic factors that affect site-specific catalysis by this class of endonucleases. The relationship between DNA sequence recognition and catalytic specificity in a DNA-modifying enzyme was explored using paramagnetic Cu 2+ ions as probes for ESR spectroscopic and biochemical studies. Electron spin echo envelope modulation spectroscopy establishes that Cu 2+ coordinates to histidine residues in the EcoRI endonuclease homodimer bound to its specific DNA recognition site. The coordinated His residues were identified by a unique use of Cu 2+ -ion based long-range distance constraints. Double electron-electron resonance data yield Cu 2+ -Cu 2+ and Cu 2+ -nitroxide distances that are uniquely consistent with one Cu 2+ bound to His114 in each subunit. Isothermal titration calorimetry confirms that two Cu 2+ ions bind per complex. Unexpectedly, Mg 2+ -catalyzed DNA cleavage by EcoRI is profoundly inhibited by Cu 2+ binding at these hitherto unknown sites, 13 Å away from the Mg 2+ positions in the catalytic centers. Molecular dynamics simulations suggest a model for inhibition of catalysis, whereby the Cu 2+ ions alter critical protein-DNA interactions and water molecule positions in the catalytic sites. In the absence of Cu 2+ , the Mg 2+ -dependence of EcoRI catalysis shows positive cooperativity, which would enhance EcoRI inactivation of foreign DNA by irreparable double-strand cuts, in preference to readily repaired single-strand nicks. Nonlinear Poisson-Boltzmann calculations suggest that this cooperativity arises because the binding of Mg 2+ in one catalytic site makes the surface electrostatic potential in the distal catalytic site more negative, thus enhancing binding of the second Mg 2+ . Taken together, our results shed light on the structural and electrostatic factors that affect site-specific catalysis by this class of endonucleases. |
| Author | Kurpiewski, Michael R Townsend, Jacque E Jen-Jacobson, Linda Mehta, Preeti Ji, Ming Saxena, Sunil Yang, Zhongyu |
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| Notes | http://dx.doi.org/10.1073/pnas.1200733109 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1 Edited by Brian M. Hoffman, Northwestern University, Evanston, IL, and approved March 9, 2012 (received for review January 18, 2012) 3Present address: Department of Biochemistry, Stony Brook University, Stony Brook, NY 11794. Author contributions: L.J.-J. and S.S. designed research; Z.Y., M.R.K., M.J., J.E.T., and P.M. performed research; Z.Y., M.R.K., M.J., J.E.T., L.J.-J., and S.S. analyzed data; and Z.Y., M.J., L.J.-J., and S.S. wrote the paper. 1Z.Y., M.R.K., and M.J. contributed equally to this work. 2Present address: Jules Stein Eye Institute and Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095. |
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| Snippet | The relationship between DNA sequence recognition and catalytic specificity in a DNA-modifying enzyme was explored using paramagnetic Cu2+ ions as probes for... The relationship between DNA sequence recognition and catalytic specificity in a DNA-modifying enzyme was explored using paramagnetic Cu 2+ ions as probes for... The relationship between DNA sequence recognition and catalytic specificity in a DNA-modifying enzyme was explored using paramagnetic Cu(2+) ions as probes for... The relationship between DNA sequence recognition and catalytic specificity in a DNA-modifying enzyme was explored using paramagnetic Cu 2+ ions as probes for... |
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| StartPage | E993 |
| SubjectTerms | Biocatalysis Biological Sciences calorimetry catalytic activity Catalytic Domain chemistry Copper Copper - metabolism Dimerization DNA DNA - metabolism DNA Modification Methylases DNA Modification Methylases - chemistry DNA Modification Methylases - metabolism Electron Spin Resonance Spectroscopy Electron Spin Resonance Spectroscopy - methods histidine Histidine - metabolism ions magnesium metabolism methods molecular dynamics Molecular Dynamics Simulation nucleotide sequences Physical Sciences PNAS Plus spectroscopy titration |
| Title | ESR spectroscopy identifies inhibitory Cu2+ sites in a DNA-modifying enzyme to reveal determinants of catalytic specificity |
| URI | http://www.pnas.org/content/109/17/E993.abstract https://www.ncbi.nlm.nih.gov/pubmed/22493217 https://www.proquest.com/docview/1009801936 https://www.proquest.com/docview/1020837715 https://www.proquest.com/docview/1663523650 https://pubmed.ncbi.nlm.nih.gov/PMC3340070 |
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