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• W2030658423 abstract "MtaN (Multidrug Transporter Activation, N terminus) is a constitutive, transcriptionally active 109-residue truncation mutant, which contains only the N-terminal DNA-binding and dimerization domains of MerR family member Mta. The 2.75 Å resolution crystal structure of apo-MtaN reveals a winged helix-turn-helix protein with a protruding 8-turn helix (α5) that is involved in dimerization by the formation of an antiparallel coiled-coil. The hydrophobic core and helices α1 through α4 are structurally homologous to MerR family member BmrR bound to DNA, whereas one wing (Wing 1) is shifted. Differences between the orientation of α5 with respect to the core and the revolution of the antiparallel coiled-coil lead to significantly altered conformations of MtaN and BmrR dimers. These shifts result in a conformation of MtaN that appears to be incompatible with the transcription activation mechanism of BmrR and suggest that additional DNA-induced structural changes are necessary. MtaN (Multidrug Transporter Activation, N terminus) is a constitutive, transcriptionally active 109-residue truncation mutant, which contains only the N-terminal DNA-binding and dimerization domains of MerR family member Mta. The 2.75 Å resolution crystal structure of apo-MtaN reveals a winged helix-turn-helix protein with a protruding 8-turn helix (α5) that is involved in dimerization by the formation of an antiparallel coiled-coil. The hydrophobic core and helices α1 through α4 are structurally homologous to MerR family member BmrR bound to DNA, whereas one wing (Wing 1) is shifted. Differences between the orientation of α5 with respect to the core and the revolution of the antiparallel coiled-coil lead to significantly altered conformations of MtaN and BmrR dimers. These shifts result in a conformation of MtaN that appears to be incompatible with the transcription activation mechanism of BmrR and suggest that additional DNA-induced structural changes are necessary. multidrug resistance multidrug transporter activation, N terminus base pair(s) root mean-squared deviation multiwavelength anomalous diffraction bacterial multidrug resistance regulator Bacterial multidrug resistance (MDR)1 is a growing threat to human health. One key component of MDR is the efflux of structurally and chemically diverse compounds, including antibiotics, antiseptics, and disinfectants, by membrane-bound multidrug transporters (1Paulsen I.T. Brown M.H. Skurray R.A. Microbiol. Rev. 1996; 60: 575-608Crossref PubMed Google Scholar, 2van Veen H.W. Putman M. Margolles A. Sakamoto K. Konings W.N. Biochim. Biophys. Acta. 1999; 1461: 201-206Crossref PubMed Scopus (29) Google Scholar). Although often regulated by global regulators (3Grkovic S. Brown M.H. Skurray R.A. Semin Cell Dev. Biol. 2001; 12: 225-237Crossref PubMed Scopus (74) Google Scholar, 4Putman M. van Veen H.W. Konings W.N. Microbiol. Mol. Biol. Rev. 2000; 64: 672-693Crossref PubMed Scopus (630) Google Scholar) such as MarA (5Rhee S. Martin R.G. Rosner J.L. Davies D.R. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 10413-10418Crossref PubMed Scopus (230) Google Scholar), which activates over a dozen genes (6Alekshun M.N. Levy S.B. Antimicrob. Agents Chemother. 1997; 41: 2067-2075Crossref PubMed Google Scholar, 7Barbosa T.M. Levy S.B. J. Bacteriol. 2000; 182: 3467-3474Crossref PubMed Scopus (288) Google Scholar), many MDR genes are regulated specifically, such as qacA by QacR (8Grkovic S. Brown M.H. Roberts N.J. Paulsen I.T. Skurray R.A. J. Biol. Chem. 1998; 273: 18665-18673Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar) and emrABby EmrR (9Lomovskaya O. Lewis K. Matin A. J. Bacteriol. 1995; 177: 2328-2334Crossref PubMed Scopus (203) Google Scholar). In Bacillus subtilis, BmrR (10Ahmed M. Borsch C.M. Taylor S.S. Vazquez-Laslop N. Neyfakh A.A. J. Biol. Chem. 1994; 269: 28506-28513Abstract Full Text PDF PubMed Google Scholar) and BltR (11Ahmed M. Lyass L. Markham P.N. Taylor S.S. Vazquez-Laslop N. Neyfakh A.A. J. Bacteriol. 1995; 177: 3904-3910Crossref PubMed Scopus (145) Google Scholar), members of the MerR family (12Summers A.O. J. Bacteriol. 1992; 174: 3097-3101Crossref PubMed Scopus (181) Google Scholar), regulate transcription of the MDR transporter genes bmr and blt, respectively. MtaN (multidrug transporter activation, N terminus), another MerR family member, is a global activator ofB. subtilis multidrug transporter genes and constitutively activates transcription of bmr and blt, another putative membrane protein gene (ydfK) and its own gene (13Baranova N.N. Danchin A. Neyfakh A.A. Mol. Microbiol. 1999; 31: 1549-1559Crossref PubMed Scopus (56) Google Scholar).MerR proteins range from relatively small size, such as theEscherichia coli MerR (144 residues per monomer) andE. coli ZntR (141 residues), to those over a hundred amino acid residues longer including B. subtilis BmrR (278 residues) or Streptomyces lividans TipAL (253 residues). These proteins form homodimers that regulate genes to combat a variety of cellular stresses. ZntR (14Outten C.E. Outten F.W. O'Halloran T.V. J. Biol. Chem. 1999; 274: 37517-37524Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar), CueR (15Outten F.W. Outten C.E. Hale J. O'Halloran T.V. J. Biol. Chem. 2000; 275: 31024-31029Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar), PMTR (16Noll M. Petrukhin K. Lutsenko S. J. Biol. Chem. 1998; 273: 21393-21401Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar), and MerR (12Summers A.O. J. Bacteriol. 1992; 174: 3097-3101Crossref PubMed Scopus (181) Google Scholar) bind divalent metal ions to activate their respective metal resistance systems, whereas SoxR responds to oxidative stress through redox disassembly of its iron-sulfur centers (17Hidalgo E. Ding H. Demple B. Trends Biochem. Sci. 1997; 22: 207-210Abstract Full Text PDF PubMed Scopus (113) Google Scholar). NolA is involved in the nodulation process in Bradyrhizobium japonicum by responding to nodulation factors from soybeans (18Sadowsky M.J. Cregan P.B. Gottfert M. Sharma A. Gerhold D. Rodriguez-Quinones F. Keyser H.H. Hennecke H. Stacey G. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 637-641Crossref PubMed Scopus (84) Google Scholar). BmrR binds toxic lipophilic cations, although physiologically relevant ligand(s) of BmrR have yet to be identified (10Ahmed M. Borsch C.M. Taylor S.S. Vazquez-Laslop N. Neyfakh A.A. J. Biol. Chem. 1994; 269: 28506-28513Abstract Full Text PDF PubMed Google Scholar). TipAL covalently binds the large antibiotic thiostrepton (19Holmes D.J. Caso J.L. Thompson C.J. EMBO J. 1993; 12: 3183-3191Crossref PubMed Scopus (116) Google Scholar). Whereas MtaN is able to activate transcription of multidrug transporters and full-length Mta is closely related (40% sequence identity) to TipAL, Mta is not induced by thiostrepton (13Baranova N.N. Danchin A. Neyfakh A.A. Mol. Microbiol. 1999; 31: 1549-1559Crossref PubMed Scopus (56) Google Scholar), and the ligand or ligands of Mta remain unknown.The N-terminal domain of each MerR subunit, the most conserved segment, contains a winged helix-turn-helix motif (20Shewchuk L.M. Helmann J.D. Ross W. Park S.J. Summers A.O. Walsh C.T. Biochemistry. 1989; 28: 2340-2344Crossref PubMed Scopus (43) Google Scholar) and the dimerization region, which comprises half of an antiparallel coiled-coil (21Caguiat J.J. Watson A.L. Summers A.O. J. Bacteriol. 1999; 181: 3462-3471Crossref PubMed Google Scholar). This ∼110-residue domain is the signature of the MerR family, and it is likely to be structurally and functionally conserved. Beyond the winged helix-turn-helix motif, there appears to be no significant sequence or structural homology between MerR family members and other known gene regulators. The variable length C-terminal domain of MerR proteins contains ligand or coactivator binding elements that have been tailored to recognize their widely divergent and non-overlapping signals. Not surprisingly, the larger proteins bind larger coactivators, whereas the smaller proteins appear to be the minimum size necessary to respond to a divalent cation.The function of the C terminus is to modulate the transcriptional activation of MerR family members by keeping the protein/DNA complex in a transcriptionally inactive form until a coactivator is bound, at which time repression is relieved, and the protein is able to up-regulate transcription (13Baranova N.N. Danchin A. Neyfakh A.A. Mol. Microbiol. 1999; 31: 1549-1559Crossref PubMed Scopus (56) Google Scholar, 22Godsey M.H. Baranova N.N. Neyfakh A.A. Brennan R.G. Acta Crystallogr. Sect. D. 2000; 56: 1456-1458Crossref PubMed Scopus (3) Google Scholar). MtaN is an unusual MerR family member because the protein lacks this modulation domain, which leads to its constitutive activation of cognate promoters (13Baranova N.N. Danchin A. Neyfakh A.A. Mol. Microbiol. 1999; 31: 1549-1559Crossref PubMed Scopus (56) Google Scholar). Because MtaN constitutively activates its own transcription, cells containingmtaN produce high levels of this protein through positive feedback. Eventually, elevated levels of MtaN overcome its lower affinities for the bmr and blt promoters, and those genes are activated (13Baranova N.N. Danchin A. Neyfakh A.A. Mol. Microbiol. 1999; 31: 1549-1559Crossref PubMed Scopus (56) Google Scholar). MtaN appears to represent the smallest active form of the MerR family of transcriptional regulators.An unusual feature of the genes that are regulated by MerR family members is the 19-base pair (bp) separation of the −10 and −35 promoter elements (23Parkhill J. Brown N.L. Nucleic Acids Res. 1990; 18: 5157-5162Crossref PubMed Scopus (54) Google Scholar), which is 17 bp in most bacterial promoters (24Helmann J.D. Nucleic Acids Res. 1995; 23: 2351-2360Crossref PubMed Scopus (329) Google Scholar,25McClure W.R. Annu. Rev. Biochem. 1985; 54: 171-204Crossref PubMed Scopus (717) Google Scholar). The 19-bp spacer appears to prevent open complex formation by RNA polymerase in the absence of an activator (23Parkhill J. Brown N.L. Nucleic Acids Res. 1990; 18: 5157-5162Crossref PubMed Scopus (54) Google Scholar). This unusual promoter structure has led to a model of transcription regulation by these proteins in which activation is achieved by DNA distortion and untwisting (12Summers A.O. J. Bacteriol. 1992; 174: 3097-3101Crossref PubMed Scopus (181) Google Scholar, 26Ansari A.Z. Chael M.L. O'Halloran T.V. Nature. 1992; 355: 87-89Crossref PubMed Scopus (137) Google Scholar). The recent crystal structure of BmrR bound to DNA and coactivator has delineated a significant portion of the activation mechanism (27Zheleznova-Heldwein E.E. Brennan R.G. Nature. 2001; 409: 378-382Crossref PubMed Scopus (217) Google Scholar). The ternary complex shows that the center of the DNA-binding site is bent, untwisted, and bunched-up, shortening the effective length of the DNA and reconfiguring the RNA polymerase binding sites to resemble more closely a 17-bp spacer and allow open complex formation.The BmrR-drug-DNA complex provides insight into one facet of transcription regulation by the MerR family. However, the extent of the conformational changes of these proteins needed to effect DNA binding and transcription activation, if any, are unknown. To address this aspect of the mechanism of MerR family transcription activation, we solved the crystal structure of MtaN to 2.75 Å resolution. Comparison of the structures of MtaN and DNA/drug-bound BmrR reveals their overall structural similarity, as well as significant tertiary and quaternary differences. Bacterial multidrug resistance (MDR)1 is a growing threat to human health. One key component of MDR is the efflux of structurally and chemically diverse compounds, including antibiotics, antiseptics, and disinfectants, by membrane-bound multidrug transporters (1Paulsen I.T. Brown M.H. Skurray R.A. Microbiol. Rev. 1996; 60: 575-608Crossref PubMed Google Scholar, 2van Veen H.W. Putman M. Margolles A. Sakamoto K. Konings W.N. Biochim. Biophys. Acta. 1999; 1461: 201-206Crossref PubMed Scopus (29) Google Scholar). Although often regulated by global regulators (3Grkovic S. Brown M.H. Skurray R.A. Semin Cell Dev. Biol. 2001; 12: 225-237Crossref PubMed Scopus (74) Google Scholar, 4Putman M. van Veen H.W. Konings W.N. Microbiol. Mol. Biol. Rev. 2000; 64: 672-693Crossref PubMed Scopus (630) Google Scholar) such as MarA (5Rhee S. Martin R.G. Rosner J.L. Davies D.R. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 10413-10418Crossref PubMed Scopus (230) Google Scholar), which activates over a dozen genes (6Alekshun M.N. Levy S.B. Antimicrob. Agents Chemother. 1997; 41: 2067-2075Crossref PubMed Google Scholar, 7Barbosa T.M. Levy S.B. J. Bacteriol. 2000; 182: 3467-3474Crossref PubMed Scopus (288) Google Scholar), many MDR genes are regulated specifically, such as qacA by QacR (8Grkovic S. Brown M.H. Roberts N.J. Paulsen I.T. Skurray R.A. J. Biol. Chem. 1998; 273: 18665-18673Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar) and emrABby EmrR (9Lomovskaya O. Lewis K. Matin A. J. Bacteriol. 1995; 177: 2328-2334Crossref PubMed Scopus (203) Google Scholar). In Bacillus subtilis, BmrR (10Ahmed M. Borsch C.M. Taylor S.S. Vazquez-Laslop N. Neyfakh A.A. J. Biol. Chem. 1994; 269: 28506-28513Abstract Full Text PDF PubMed Google Scholar) and BltR (11Ahmed M. Lyass L. Markham P.N. Taylor S.S. Vazquez-Laslop N. Neyfakh A.A. J. Bacteriol. 1995; 177: 3904-3910Crossref PubMed Scopus (145) Google Scholar), members of the MerR family (12Summers A.O. J. Bacteriol. 1992; 174: 3097-3101Crossref PubMed Scopus (181) Google Scholar), regulate transcription of the MDR transporter genes bmr and blt, respectively. MtaN (multidrug transporter activation, N terminus), another MerR family member, is a global activator ofB. subtilis multidrug transporter genes and constitutively activates transcription of bmr and blt, another putative membrane protein gene (ydfK) and its own gene (13Baranova N.N. Danchin A. Neyfakh A.A. Mol. Microbiol. 1999; 31: 1549-1559Crossref PubMed Scopus (56) Google Scholar). MerR proteins range from relatively small size, such as theEscherichia coli MerR (144 residues per monomer) andE. coli ZntR (141 residues), to those over a hundred amino acid residues longer including B. subtilis BmrR (278 residues) or Streptomyces lividans TipAL (253 residues). These proteins form homodimers that regulate genes to combat a variety of cellular stresses. ZntR (14Outten C.E. Outten F.W. O'Halloran T.V. J. Biol. Chem. 1999; 274: 37517-37524Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar), CueR (15Outten F.W. Outten C.E. Hale J. O'Halloran T.V. J. Biol. Chem. 2000; 275: 31024-31029Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar), PMTR (16Noll M. Petrukhin K. Lutsenko S. J. Biol. Chem. 1998; 273: 21393-21401Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar), and MerR (12Summers A.O. J. Bacteriol. 1992; 174: 3097-3101Crossref PubMed Scopus (181) Google Scholar) bind divalent metal ions to activate their respective metal resistance systems, whereas SoxR responds to oxidative stress through redox disassembly of its iron-sulfur centers (17Hidalgo E. Ding H. Demple B. Trends Biochem. Sci. 1997; 22: 207-210Abstract Full Text PDF PubMed Scopus (113) Google Scholar). NolA is involved in the nodulation process in Bradyrhizobium japonicum by responding to nodulation factors from soybeans (18Sadowsky M.J. Cregan P.B. Gottfert M. Sharma A. Gerhold D. Rodriguez-Quinones F. Keyser H.H. Hennecke H. Stacey G. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 637-641Crossref PubMed Scopus (84) Google Scholar). BmrR binds toxic lipophilic cations, although physiologically relevant ligand(s) of BmrR have yet to be identified (10Ahmed M. Borsch C.M. Taylor S.S. Vazquez-Laslop N. Neyfakh A.A. J. Biol. Chem. 1994; 269: 28506-28513Abstract Full Text PDF PubMed Google Scholar). TipAL covalently binds the large antibiotic thiostrepton (19Holmes D.J. Caso J.L. Thompson C.J. EMBO J. 1993; 12: 3183-3191Crossref PubMed Scopus (116) Google Scholar). Whereas MtaN is able to activate transcription of multidrug transporters and full-length Mta is closely related (40% sequence identity) to TipAL, Mta is not induced by thiostrepton (13Baranova N.N. Danchin A. Neyfakh A.A. Mol. Microbiol. 1999; 31: 1549-1559Crossref PubMed Scopus (56) Google Scholar), and the ligand or ligands of Mta remain unknown. The N-terminal domain of each MerR subunit, the most conserved segment, contains a winged helix-turn-helix motif (20Shewchuk L.M. Helmann J.D. Ross W. Park S.J. Summers A.O. Walsh C.T. Biochemistry. 1989; 28: 2340-2344Crossref PubMed Scopus (43) Google Scholar) and the dimerization region, which comprises half of an antiparallel coiled-coil (21Caguiat J.J. Watson A.L. Summers A.O. J. Bacteriol. 1999; 181: 3462-3471Crossref PubMed Google Scholar). This ∼110-residue domain is the signature of the MerR family, and it is likely to be structurally and functionally conserved. Beyond the winged helix-turn-helix motif, there appears to be no significant sequence or structural homology between MerR family members and other known gene regulators. The variable length C-terminal domain of MerR proteins contains ligand or coactivator binding elements that have been tailored to recognize their widely divergent and non-overlapping signals. Not surprisingly, the larger proteins bind larger coactivators, whereas the smaller proteins appear to be the minimum size necessary to respond to a divalent cation. The function of the C terminus is to modulate the transcriptional activation of MerR family members by keeping the protein/DNA complex in a transcriptionally inactive form until a coactivator is bound, at which time repression is relieved, and the protein is able to up-regulate transcription (13Baranova N.N. Danchin A. Neyfakh A.A. Mol. Microbiol. 1999; 31: 1549-1559Crossref PubMed Scopus (56) Google Scholar, 22Godsey M.H. Baranova N.N. Neyfakh A.A. Brennan R.G. Acta Crystallogr. Sect. D. 2000; 56: 1456-1458Crossref PubMed Scopus (3) Google Scholar). MtaN is an unusual MerR family member because the protein lacks this modulation domain, which leads to its constitutive activation of cognate promoters (13Baranova N.N. Danchin A. Neyfakh A.A. Mol. Microbiol. 1999; 31: 1549-1559Crossref PubMed Scopus (56) Google Scholar). Because MtaN constitutively activates its own transcription, cells containingmtaN produce high levels of this protein through positive feedback. Eventually, elevated levels of MtaN overcome its lower affinities for the bmr and blt promoters, and those genes are activated (13Baranova N.N. Danchin A. Neyfakh A.A. Mol. Microbiol. 1999; 31: 1549-1559Crossref PubMed Scopus (56) Google Scholar). MtaN appears to represent the smallest active form of the MerR family of transcriptional regulators. An unusual feature of the genes that are regulated by MerR family members is the 19-base pair (bp) separation of the −10 and −35 promoter elements (23Parkhill J. Brown N.L. Nucleic Acids Res. 1990; 18: 5157-5162Crossref PubMed Scopus (54) Google Scholar), which is 17 bp in most bacterial promoters (24Helmann J.D. Nucleic Acids Res. 1995; 23: 2351-2360Crossref PubMed Scopus (329) Google Scholar,25McClure W.R. Annu. Rev. Biochem. 1985; 54: 171-204Crossref PubMed Scopus (717) Google Scholar). The 19-bp spacer appears to prevent open complex formation by RNA polymerase in the absence of an activator (23Parkhill J. Brown N.L. Nucleic Acids Res. 1990; 18: 5157-5162Crossref PubMed Scopus (54) Google Scholar). This unusual promoter structure has led to a model of transcription regulation by these proteins in which activation is achieved by DNA distortion and untwisting (12Summers A.O. J. Bacteriol. 1992; 174: 3097-3101Crossref PubMed Scopus (181) Google Scholar, 26Ansari A.Z. Chael M.L. O'Halloran T.V. Nature. 1992; 355: 87-89Crossref PubMed Scopus (137) Google Scholar). The recent crystal structure of BmrR bound to DNA and coactivator has delineated a significant portion of the activation mechanism (27Zheleznova-Heldwein E.E. Brennan R.G. Nature. 2001; 409: 378-382Crossref PubMed Scopus (217) Google Scholar). The ternary complex shows that the center of the DNA-binding site is bent, untwisted, and bunched-up, shortening the effective length of the DNA and reconfiguring the RNA polymerase binding sites to resemble more closely a 17-bp spacer and allow open complex formation. The BmrR-drug-DNA complex provides insight into one facet of transcription regulation by the MerR family. However, the extent of the conformational changes of these proteins needed to effect DNA binding and transcription activation, if any, are unknown. To address this aspect of the mechanism of MerR family transcription activation, we solved the crystal structure of MtaN to 2.75 Å resolution. Comparison of the structures of MtaN and DNA/drug-bound BmrR reveals their overall structural similarity, as well as significant tertiary and quaternary differences. We thank E. E. Zheleznova-Heldwein for sharing the BmrR coordinates with us prior to publication. Portions of this research were carried out at the Stanford Synchrotron Radiation Laboratory, a national user facility operated by Stanford University on behalf of the United States Department of Energy, Office of Basic Energy Sciences. The SSRL Structural Molecular Biology Program is supported by the Department of Energy, Office of Biological and Environmental Research and by the National Institutes of Health, National Center for Research Resources, Biomedical Technology Program, and the National Institute of General Medical Sciences." @default.
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• W2030658423 date "2001-12-01" @default.
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• W2030658423 title "Crystal Structure of MtaN, a Global Multidrug Transporter Gene Activator" @default.
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