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• W2073912176 abstract "The catalytic efficiency of incorporation of deoxyribonucleotides by wild-type human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) was around 100-fold higher than for dideoxyribonucleotides, in Mg2+-catalyzed reactions, and more than 10,000-fold higher than for nucleotides having a 2′-hydroxyl group in Mg2+- and Mn2+-catalyzed reactions. Mutant RTs with nonconservative substitutions affecting Tyr-115 (Y115V, Y115A, and Y115G) showed a dramatic reduction in their ability to discriminate against ribonucleotides in the presence of both cations. However, selectivity of deoxyribonucleotidesversus ribonucleotides was not affected in mutants Y115W and F160W. The substitution of Tyr-115 with Val or Gly had no effect on discrimination against dideoxyribonucleotides, but these mutants were less efficient than the wild-type RT in discriminating against cordycepin 5′-triphosphate. We also show that Tyr-115 is involved in fidelity of DNA synthesis, but substitutions at this position have different effects depending on the metal cofactor used in the assays. In Mg2+-catalyzed reactions, removal of the side chain of Tyr-115 reduced misinsertion and mispair extension fidelity, while opposite effects were observed in Mn2+-catalyzed reactions. Our results indicate that the aromatic side chain of Tyr-115 plays a role as a “steric gate” preventing the incorporation of nucleotides with a 2′-hydroxyl group in a cation-independent manner, while its influence on fidelity could be modulated by Mg2+ or Mn2+. The catalytic efficiency of incorporation of deoxyribonucleotides by wild-type human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) was around 100-fold higher than for dideoxyribonucleotides, in Mg2+-catalyzed reactions, and more than 10,000-fold higher than for nucleotides having a 2′-hydroxyl group in Mg2+- and Mn2+-catalyzed reactions. Mutant RTs with nonconservative substitutions affecting Tyr-115 (Y115V, Y115A, and Y115G) showed a dramatic reduction in their ability to discriminate against ribonucleotides in the presence of both cations. However, selectivity of deoxyribonucleotidesversus ribonucleotides was not affected in mutants Y115W and F160W. The substitution of Tyr-115 with Val or Gly had no effect on discrimination against dideoxyribonucleotides, but these mutants were less efficient than the wild-type RT in discriminating against cordycepin 5′-triphosphate. We also show that Tyr-115 is involved in fidelity of DNA synthesis, but substitutions at this position have different effects depending on the metal cofactor used in the assays. In Mg2+-catalyzed reactions, removal of the side chain of Tyr-115 reduced misinsertion and mispair extension fidelity, while opposite effects were observed in Mn2+-catalyzed reactions. Our results indicate that the aromatic side chain of Tyr-115 plays a role as a “steric gate” preventing the incorporation of nucleotides with a 2′-hydroxyl group in a cation-independent manner, while its influence on fidelity could be modulated by Mg2+ or Mn2+. human immunodeficiency virus type 1 reverse transcriptase deoxyribonucleoside triphosphate Moloney murine leukemia virus wild-type ribonucleoside triphosphate dideoxyribonucleoside triphosphate The human immunodeficiency virus type 1 (HIV-1)1 reverse transcriptase (RT) is a virally encoded enzyme. It converts the viral single-stranded RNA into double-stranded DNA which integrates into the host genome. The enzyme is multifunctional, possessing RNA- and DNA-dependent DNA polymerase, RNase H, strand transfer, and strand displacement activities (1.Telesnitsky A. Goff S.P. Coffin J. Hughes S.H. Varmus H. Retroviruses. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY1997: 121-160Google Scholar, 2.Arts E.J. Le Grice S.F.J. Progr. Nucleic Acids Res. Mol. Biol. 1998; 58: 339-393Crossref PubMed Scopus (77) Google Scholar). The HIV-1 RT is an error prone enzyme, as manifested by the frequencies of base substitutions, −1 frameshifts, and complex errors in the polymerization products (3.Bebenek K. Kunkel T.A. Skalka A.M. Goff S.P. Reverse Transcriptase. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY1993: 85-102Google Scholar, 4.Preston B.D. Dougherty J.P. Trends Microbiol. 1996; 4: 16-21Abstract Full Text PDF PubMed Scopus (119) Google Scholar). Unlike other DNA polymerases (e.g. Escherichia coli DNA polymerases I and III, T4 DNA polymerase, chicken polymerase γ, or calf polymerase δ, among others), retroviral RTs lack a proofreading activity. The low fidelity of HIV-1 RT contributes to retroviral mutagenesis and promotes the emergence of variants escaping the host's immune response, as well as viruses that are resistant to antiretroviral drugs such as RT or protease inhibitors.The HIV-1 RT is a heterodimer composed of two subunits of 66 and 51 kDa, with subdomains termed fingers, thumb, and palm and connection in both subunits and an RNase H domain in the larger subunit only. The polymerase active site resides within the palm subdomain of the 66-kDa subunit, which bears the catalytic aspartic acid residues 110, 185, and 186. A crystal structure of a covalently trapped catalytic complex of HIV-1 RT containing a DNA template-primer and a deoxyribonucleoside triphosphate (dNTP) has been reported (5.Huang H. Chopra R. Verdine G.L. Harrison S.C. Science. 1998; 282: 1669-1675Crossref PubMed Scopus (1353) Google Scholar). According to this structure, the triphosphate moiety of the dNTP is coordinated by the side chains of Lys-65 and Arg-72, the main chains of Asp-113 and Ala-114, and two magnesium ions. The side chains of Arg-72 and Gln-151 pack against the outer surface of the incoming dNTP, and the ribose moiety of the incoming dNTP binds in a pocket defined by the side chains of Asp-113, Tyr-115, Phe-116, and Gln-151. Non-conservative substitutions at residues involved in dNTP binding are usually detrimental for polymerase activity and viral replication (6.Larder B.A. Kemp S.D. Purifoy D.J.M. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 4803-4807Crossref PubMed Scopus (127) Google Scholar, 7.Wakefield J.K. Jablonski S.A. Morrow C.D. J. Virol. 1992; 66: 6806-6812Crossref PubMed Google Scholar, 8.Gutiérrez-Rivas M. Ibáñez A. Martı́nez M.A. Domingo E. Menéndez-Arias L. J. Mol. Biol. 1999; 290: 615-625Crossref PubMed Scopus (24) Google Scholar, 9.Olivares I. Sánchez-Merino V. Martı́nez M.A. Domingo E. López- Galı́ndez C. Menéndez-Arias L. J. Virol. 1999; 73: 6293-6298Crossref PubMed Google Scholar).Enzymatic characterization of recombinant HIV-1 RT variants led to the identification of mutations affecting Tyr-115 and other residues in its vicinity (e.g. Gln-151, Phe-160, Tyr-183, or Met-184) that influenced dNTP binding (8.Gutiérrez-Rivas M. Ibáñez A. Martı́nez M.A. Domingo E. Menéndez-Arias L. J. Mol. Biol. 1999; 290: 615-625Crossref PubMed Scopus (24) Google Scholar, 10.Sarafianos S.G. Pandey V.N. Kaushik N. Modak M.J. Biochemistry. 1995; 34: 7207-7216Crossref PubMed Scopus (56) Google Scholar, 11.Martı́n-Hernández A.M. Domingo E. Menéndez-Arias L. EMBO J. 1996; 15: 4434-4442Crossref PubMed Scopus (70) Google Scholar, 12.Wilson J.E. Aulabaugh A. Caligan B. McPherson S. Wakefield J.K. Jablonski S. Morrow C.D. Reardon J.E. Furman P.A. J. Biol. Chem. 1996; 271: 13656-13662Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, 13.Martı́n-Hernández A.M. Gutiérrez-Rivas M. Domingo E. Menéndez-Arias L. Nucleic Acids Res. 1997; 25: 1383-1389Crossref PubMed Scopus (52) Google Scholar, 14.Harris D. Kaushik N. Pandey P.K. Yadav P.N.S. Pandey V.N. J. Biol. Chem. 1998; 273: 33624-33634Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar, 15.Harris D. Yadav P.N.S. Pandey V.N. Biochemistry. 1998; 37: 9630-9640Crossref PubMed Scopus (40) Google Scholar). In the case of Tyr-115, its replacement with Phe rendered RT fully active, although other amino acid changes such as Y115W, Y115V, Y115A, or Y115G diminished the polymerase activity of the enzyme, by increasing theK m values for the incorporation of dNTPs (11.Martı́n-Hernández A.M. Domingo E. Menéndez-Arias L. EMBO J. 1996; 15: 4434-4442Crossref PubMed Scopus (70) Google Scholar, 13.Martı́n-Hernández A.M. Gutiérrez-Rivas M. Domingo E. Menéndez-Arias L. Nucleic Acids Res. 1997; 25: 1383-1389Crossref PubMed Scopus (52) Google Scholar). Based on the crystallographic data, it has been suggested that the side chain of Tyr-115 is important for modifications at the 2′ and 3′ positions of the dNTP. In support of this proposal, the substitution of Val for the equivalent residue of Moloney murine leukemia virus (Mo-MLV) RT (Phe-155) rendered an enzyme with a dramatically increased affinity for ribonucleotides, compared with the wild-type (WT) RT (16.Gao G. Orlova M. Georgiadis M.M. Hendrickson W.A. Goff S.P. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 407-411Crossref PubMed Scopus (162) Google Scholar). Unlike in the case of HIV-1 RT, the introduced mutation did not alter the affinity for dTTP. However, the kinetic parameters reported for HIV-1 RT were determined in the presence of magnesium cations (Mg2+), while in the case of Mo-MLV, manganese cations (Mn2+) were used as cofactors.The consequence of replacing Mg2+ with Mn2+ in DNA polymerization was originally documented by Hall and Lehman (17.Hall Z.W. Lehman I.R. J. Mol. Biol. 1968; 36: 321-333Crossref PubMed Scopus (103) Google Scholar), who showed that Mn2+ caused the phage T4 DNA polymerase to be error prone. Evidence of increased error frequency in the presence of Mn2+ has been observed in vitro withEscherichia coli DNA polymerase I (18.El-Deiry W.S. Downey K.M. So A.G. Proc. Natl. Acad. Sci. U. S. A. 1984; 81: 7378-7382Crossref PubMed Scopus (78) Google Scholar, 19.Beckman R.A. Mildvan A.S. Loeb L.A. Biochemistry. 1985; 24: 5810-5817Crossref PubMed Scopus (166) Google Scholar, 20.El-Deiry W.S. So A.G. Downey K.M. Biochemistry. 1988; 27: 546-553Crossref PubMed Scopus (22) Google Scholar, 21.Eger B.T. Kuchta R.D. Carroll S.S. Benkovic P.A. Dahlberg M.E. Joyce C.M. Benkovic S.J. Biochemistry. 1991; 30: 1441-1448Crossref PubMed Scopus (88) Google Scholar, 22.Ricchetti M. Buc H. EMBO J. 1993; 12: 387-396Crossref PubMed Scopus (52) Google Scholar), T4 DNA polymerase (23.Goodman M.F. Keener S. Guidotti S. Branscomb E.W. J. Biol. Chem. 1983; 258: 3469-3475Abstract Full Text PDF PubMed Google Scholar), DNA polymerases α and β (24.Seal G. Shearman C.W. Loeb L.A. J. Biol. Chem. 1979; 254: 5229-5237Abstract Full Text PDF PubMed Google Scholar, 25.Copeland W.C. Lam N.K. Wang T.S.-F. J. Biol. Chem. 1993; 268: 11041-11049Abstract Full Text PDF PubMed Google Scholar, 26.Pelletier H. Sawaya M.R. Wolfle W. Wilson S.H. Kraut J. Biochemistry. 1996; 35: 12762-12777Crossref PubMed Scopus (175) Google Scholar), and avian myeloblastosis virus RT (27.Sirover M.A. Loeb L.A. J. Biol. Chem. 1977; 252: 3605-3610Abstract Full Text PDF PubMed Google Scholar). In addition, Mn2+ has been shown to induce preferential incorporation of dideoxy-versus deoxyribonucleotides in T7 DNA polymerase,Taq polymerase, and E. coli DNA polymerase I (28.Tabor S. Richardson C.C. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 4076-4080Crossref PubMed Scopus (256) Google Scholar,29.Brandis J.W. Edwards S.G. Johnson K.A. Biochemistry. 1996; 35: 2189-2200Crossref PubMed Scopus (43) Google Scholar). In this paper, we have studied the effects of Mg2+ and Mn2+ on the nucleotide specificity of HIV-1 RT, by focusing on the role of Tyr-115 in nucleotide recognition at the 2′ and 3′ positions of the ribose ring and fidelity of DNA synthesis, in Mg2+- and Mn2+-catalyzed reactions. The reported data indicate that the mutagenic effect of Mn2+ on DNA polymerization by HIV-1 RT operates mainly at the level of mispair extension. Non-conservative substitutions of Tyr-115 decrease fidelity of DNA synthesis only in Mg2+-catalyzed reactions. An aromatic amino acid residue is required at position 115 to discriminate against nucleotides having a 2′-OH group. The proposed role of Tyr-115 as a “steric gate” in HIV-1 RT does not depend on the cations used in the DNA polymerization reactions. The human immunodeficiency virus type 1 (HIV-1)1 reverse transcriptase (RT) is a virally encoded enzyme. It converts the viral single-stranded RNA into double-stranded DNA which integrates into the host genome. The enzyme is multifunctional, possessing RNA- and DNA-dependent DNA polymerase, RNase H, strand transfer, and strand displacement activities (1.Telesnitsky A. Goff S.P. Coffin J. Hughes S.H. Varmus H. Retroviruses. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY1997: 121-160Google Scholar, 2.Arts E.J. Le Grice S.F.J. Progr. Nucleic Acids Res. Mol. Biol. 1998; 58: 339-393Crossref PubMed Scopus (77) Google Scholar). The HIV-1 RT is an error prone enzyme, as manifested by the frequencies of base substitutions, −1 frameshifts, and complex errors in the polymerization products (3.Bebenek K. Kunkel T.A. Skalka A.M. Goff S.P. Reverse Transcriptase. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY1993: 85-102Google Scholar, 4.Preston B.D. Dougherty J.P. Trends Microbiol. 1996; 4: 16-21Abstract Full Text PDF PubMed Scopus (119) Google Scholar). Unlike other DNA polymerases (e.g. Escherichia coli DNA polymerases I and III, T4 DNA polymerase, chicken polymerase γ, or calf polymerase δ, among others), retroviral RTs lack a proofreading activity. The low fidelity of HIV-1 RT contributes to retroviral mutagenesis and promotes the emergence of variants escaping the host's immune response, as well as viruses that are resistant to antiretroviral drugs such as RT or protease inhibitors. The HIV-1 RT is a heterodimer composed of two subunits of 66 and 51 kDa, with subdomains termed fingers, thumb, and palm and connection in both subunits and an RNase H domain in the larger subunit only. The polymerase active site resides within the palm subdomain of the 66-kDa subunit, which bears the catalytic aspartic acid residues 110, 185, and 186. A crystal structure of a covalently trapped catalytic complex of HIV-1 RT containing a DNA template-primer and a deoxyribonucleoside triphosphate (dNTP) has been reported (5.Huang H. Chopra R. Verdine G.L. Harrison S.C. Science. 1998; 282: 1669-1675Crossref PubMed Scopus (1353) Google Scholar). According to this structure, the triphosphate moiety of the dNTP is coordinated by the side chains of Lys-65 and Arg-72, the main chains of Asp-113 and Ala-114, and two magnesium ions. The side chains of Arg-72 and Gln-151 pack against the outer surface of the incoming dNTP, and the ribose moiety of the incoming dNTP binds in a pocket defined by the side chains of Asp-113, Tyr-115, Phe-116, and Gln-151. Non-conservative substitutions at residues involved in dNTP binding are usually detrimental for polymerase activity and viral replication (6.Larder B.A. Kemp S.D. Purifoy D.J.M. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 4803-4807Crossref PubMed Scopus (127) Google Scholar, 7.Wakefield J.K. Jablonski S.A. Morrow C.D. J. Virol. 1992; 66: 6806-6812Crossref PubMed Google Scholar, 8.Gutiérrez-Rivas M. Ibáñez A. Martı́nez M.A. Domingo E. Menéndez-Arias L. J. Mol. Biol. 1999; 290: 615-625Crossref PubMed Scopus (24) Google Scholar, 9.Olivares I. Sánchez-Merino V. Martı́nez M.A. Domingo E. López- Galı́ndez C. Menéndez-Arias L. J. Virol. 1999; 73: 6293-6298Crossref PubMed Google Scholar). Enzymatic characterization of recombinant HIV-1 RT variants led to the identification of mutations affecting Tyr-115 and other residues in its vicinity (e.g. Gln-151, Phe-160, Tyr-183, or Met-184) that influenced dNTP binding (8.Gutiérrez-Rivas M. Ibáñez A. Martı́nez M.A. Domingo E. Menéndez-Arias L. J. Mol. Biol. 1999; 290: 615-625Crossref PubMed Scopus (24) Google Scholar, 10.Sarafianos S.G. Pandey V.N. Kaushik N. Modak M.J. Biochemistry. 1995; 34: 7207-7216Crossref PubMed Scopus (56) Google Scholar, 11.Martı́n-Hernández A.M. Domingo E. Menéndez-Arias L. EMBO J. 1996; 15: 4434-4442Crossref PubMed Scopus (70) Google Scholar, 12.Wilson J.E. Aulabaugh A. Caligan B. McPherson S. Wakefield J.K. Jablonski S. Morrow C.D. Reardon J.E. Furman P.A. J. Biol. Chem. 1996; 271: 13656-13662Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, 13.Martı́n-Hernández A.M. Gutiérrez-Rivas M. Domingo E. Menéndez-Arias L. Nucleic Acids Res. 1997; 25: 1383-1389Crossref PubMed Scopus (52) Google Scholar, 14.Harris D. Kaushik N. Pandey P.K. Yadav P.N.S. Pandey V.N. J. Biol. Chem. 1998; 273: 33624-33634Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar, 15.Harris D. Yadav P.N.S. Pandey V.N. Biochemistry. 1998; 37: 9630-9640Crossref PubMed Scopus (40) Google Scholar). In the case of Tyr-115, its replacement with Phe rendered RT fully active, although other amino acid changes such as Y115W, Y115V, Y115A, or Y115G diminished the polymerase activity of the enzyme, by increasing theK m values for the incorporation of dNTPs (11.Martı́n-Hernández A.M. Domingo E. Menéndez-Arias L. EMBO J. 1996; 15: 4434-4442Crossref PubMed Scopus (70) Google Scholar, 13.Martı́n-Hernández A.M. Gutiérrez-Rivas M. Domingo E. Menéndez-Arias L. Nucleic Acids Res. 1997; 25: 1383-1389Crossref PubMed Scopus (52) Google Scholar). Based on the crystallographic data, it has been suggested that the side chain of Tyr-115 is important for modifications at the 2′ and 3′ positions of the dNTP. In support of this proposal, the substitution of Val for the equivalent residue of Moloney murine leukemia virus (Mo-MLV) RT (Phe-155) rendered an enzyme with a dramatically increased affinity for ribonucleotides, compared with the wild-type (WT) RT (16.Gao G. Orlova M. Georgiadis M.M. Hendrickson W.A. Goff S.P. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 407-411Crossref PubMed Scopus (162) Google Scholar). Unlike in the case of HIV-1 RT, the introduced mutation did not alter the affinity for dTTP. However, the kinetic parameters reported for HIV-1 RT were determined in the presence of magnesium cations (Mg2+), while in the case of Mo-MLV, manganese cations (Mn2+) were used as cofactors. The consequence of replacing Mg2+ with Mn2+ in DNA polymerization was originally documented by Hall and Lehman (17.Hall Z.W. Lehman I.R. J. Mol. Biol. 1968; 36: 321-333Crossref PubMed Scopus (103) Google Scholar), who showed that Mn2+ caused the phage T4 DNA polymerase to be error prone. Evidence of increased error frequency in the presence of Mn2+ has been observed in vitro withEscherichia coli DNA polymerase I (18.El-Deiry W.S. Downey K.M. So A.G. Proc. Natl. Acad. Sci. U. S. A. 1984; 81: 7378-7382Crossref PubMed Scopus (78) Google Scholar, 19.Beckman R.A. Mildvan A.S. Loeb L.A. Biochemistry. 1985; 24: 5810-5817Crossref PubMed Scopus (166) Google Scholar, 20.El-Deiry W.S. So A.G. Downey K.M. Biochemistry. 1988; 27: 546-553Crossref PubMed Scopus (22) Google Scholar, 21.Eger B.T. Kuchta R.D. Carroll S.S. Benkovic P.A. Dahlberg M.E. Joyce C.M. Benkovic S.J. Biochemistry. 1991; 30: 1441-1448Crossref PubMed Scopus (88) Google Scholar, 22.Ricchetti M. Buc H. EMBO J. 1993; 12: 387-396Crossref PubMed Scopus (52) Google Scholar), T4 DNA polymerase (23.Goodman M.F. Keener S. Guidotti S. Branscomb E.W. J. Biol. Chem. 1983; 258: 3469-3475Abstract Full Text PDF PubMed Google Scholar), DNA polymerases α and β (24.Seal G. Shearman C.W. Loeb L.A. J. Biol. Chem. 1979; 254: 5229-5237Abstract Full Text PDF PubMed Google Scholar, 25.Copeland W.C. Lam N.K. Wang T.S.-F. J. Biol. Chem. 1993; 268: 11041-11049Abstract Full Text PDF PubMed Google Scholar, 26.Pelletier H. Sawaya M.R. Wolfle W. Wilson S.H. Kraut J. Biochemistry. 1996; 35: 12762-12777Crossref PubMed Scopus (175) Google Scholar), and avian myeloblastosis virus RT (27.Sirover M.A. Loeb L.A. J. Biol. Chem. 1977; 252: 3605-3610Abstract Full Text PDF PubMed Google Scholar). In addition, Mn2+ has been shown to induce preferential incorporation of dideoxy-versus deoxyribonucleotides in T7 DNA polymerase,Taq polymerase, and E. coli DNA polymerase I (28.Tabor S. Richardson C.C. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 4076-4080Crossref PubMed Scopus (256) Google Scholar,29.Brandis J.W. Edwards S.G. Johnson K.A. Biochemistry. 1996; 35: 2189-2200Crossref PubMed Scopus (43) Google Scholar). In this paper, we have studied the effects of Mg2+ and Mn2+ on the nucleotide specificity of HIV-1 RT, by focusing on the role of Tyr-115 in nucleotide recognition at the 2′ and 3′ positions of the ribose ring and fidelity of DNA synthesis, in Mg2+- and Mn2+-catalyzed reactions. The reported data indicate that the mutagenic effect of Mn2+ on DNA polymerization by HIV-1 RT operates mainly at the level of mispair extension. Non-conservative substitutions of Tyr-115 decrease fidelity of DNA synthesis only in Mg2+-catalyzed reactions. An aromatic amino acid residue is required at position 115 to discriminate against nucleotides having a 2′-OH group. The proposed role of Tyr-115 as a “steric gate” in HIV-1 RT does not depend on the cations used in the DNA polymerization reactions. We thank J. A. Pérez, J. I. Belio, and M. Bautista for help with the preparation of figures, and B. Canard, E. Domingo, and A. Mas for helpful discussions and critical reading of the manuscript." @default.
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• W2073912176 title "Coupling Ribose Selection to Fidelity of DNA Synthesis" @default.
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