1887

Chapter 59 : : Iron-Mediated Activation of DtxR and Regulation of Diphtheria Toxin Expression

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Ebook: Choose a downloadable PDF or ePub file. Chapter is a downloadable PDF file. File must be downloaded within 48 hours of purchase

Buy this Chapter
Digital (?) $30.00

Preview this chapter:
Zoom in
Zoomout

: Iron-Mediated Activation of DtxR and Regulation of Diphtheria Toxin Expression, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555816513/9781555813437_Chap59-1.gif /docserver/preview/fulltext/10.1128/9781555816513/9781555813437_Chap59-2.gif

Abstract:

A detailed understanding of the molecular biology and genetics of both the regulation of diphtheria toxin expression and the structure-function relationships and mode of action of the toxin is known. The existence of virulence determinants in beyond those associated with diphtheria toxin is demonstrated by the recently reported outbreak of invasive disease caused by a clonal focus of nontoxigenic among intravenous drug users in Switzerland. The regulation of expression of the gene, as well as the genes involved in iron acquisition and utilization, is under the control of the -encoded iron-activated repressor diphtheria toxin repressor (DtxR). The protein-protein interactions stabilizing DtxR dimers arise mostly from hydrophobic associations. The X-ray structure of the C-terminal domain of DtxR shows that this region of the repressor is composed of five antiparallel β-sheets and two short α-helices. Diphtheria toxin is the primary virulence factor expressed by toxigenic strains of . The structural gene encoding diphtheria toxin is carried by a family of closely related corynebacteriophages, the best studied of which is corynephage. The genome sequence has also permitted examination of microbial speciation and evolution. Outbreaks of clinical diphtheria almost always occur in individuals who have not become immunized and who have been exposed to a carrier. Molecular epidemiologic analysis of toxigenic strains of isolated from this epidemic has provided further insight into the virulence of this pathogen.

Citation: Love J, Murphy J. 2006. : Iron-Mediated Activation of DtxR and Regulation of Diphtheria Toxin Expression, p 726-737. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch59

Key Concept Ranking

Diphtheria Toxin
0.4843966
0.4843966
Highlighted Text: Show | Hide
Loading full text...

Full text loading...

Figures

Image of FIGURE 1
FIGURE 1

Expression of the diphtheria toxin structural gene, , is regulated by the Fe-activated repressor DtxR. The gene is carried on the genome of , while is carried by a family of closely related corynebacteriophages. In the presence of Fe, apo-DtxR forms active dimers [(2Fe- DtxR)], and the two dimers bind to the diphtheria operator and repress expression. Under iron-limiting conditions, the ternary complex, the 2(2Fe-DtxR)- operator, dissociates and diphtheria toxin is expressed.

Citation: Love J, Murphy J. 2006. : Iron-Mediated Activation of DtxR and Regulation of Diphtheria Toxin Expression, p 726-737. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch59
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 2
FIGURE 2

Structure of the 2[Ni DtxR(C102D)]- operator complex. Residues 3 to 120 in each DtxR(C102D) monomer are designated “a” to “d.” Ribbons and arrows are used to indicate α-helices and β-strands in each monomer. The 33-bp DNA segment carries the 27-bp interrupted palindromic operator sequence. (Adapted from White et al. [ ].)

Citation: Love J, Murphy J. 2006. : Iron-Mediated Activation of DtxR and Regulation of Diphtheria Toxin Expression, p 726-737. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch59
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 3
FIGURE 3

Amino acid sequence alignments of selected members of the DtxR superfamily. DtxR is compared to the two-domain homologs IdeR (), MntR (), EfaR (), MntR (), SirR (), and ScaR (). Residues identical in all proteins are shown as white letters with black background, while conservative differences are highlighted in grey. Circles (●) and triangles (▼) mark the residues of DtxR's primary and ancillary metal ion-binding sites, respectively. The solid square (■) above S124 of DtxR marks the end of the N-terminal domain, while two vertical lines (║) above P148 mark the beginning of the C-terminal domain, with the intervening sequence constituting the tether region. A number sign (#) marks the residues of DtxR involved in interactions with specific base pairs of target operators (S37, P39, and Q43).

Citation: Love J, Murphy J. 2006. : Iron-Mediated Activation of DtxR and Regulation of Diphtheria Toxin Expression, p 726-737. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch59
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 4
FIGURE 4

Ribbon diagram of the X-ray crystal structure of native diphtheria toxin. The relative portions of the C, T, and R domains are indicated. N, amino terminus; C, carboxy terminus.

Citation: Love J, Murphy J. 2006. : Iron-Mediated Activation of DtxR and Regulation of Diphtheria Toxin Expression, p 726-737. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch59
Permissions and Reprints Request Permissions
Download as Powerpoint

References

/content/book/10.1128/9781555816513.chap59
1. Ando, M.,, Y. C. Manabe,, P. J. Converse,, E. Miyazaki,, R. Harrison,, J. R. Murphy,, and W. R. Bishai. 2003. Characterization of the role of the divalent metal ion-dependent transcriptional repressor MntR in the virulence of Staphylococcus aureus. Infect. Immun. 71:25842590.
2. Bennett, M. J.,, S. Choe,, and D. Eisenberg. 1994. Domain swapping: entangling alliances between proteins. Proc. Natl. Acad. Sci. USA 91:31273131.
3. Bisgard, K. M.,, I. R. B. Hardy,, T. Popovic,, P. M. Strebel,, M. Wharton,, R. T. Chen,, and S. C. Hadler. 1998. Respiratory diphtheria in the United States, 1980 through 1995. Am. J. Public Health 88:787791.
4. Boland, C. A.,, and W. G. Meijer. 2000. The iron dependent regulatory protein IdeR (DtxR) of Rhodococcus equi. FEMS Microbiol. Lett. 191:15.
5. Boyd, J.,, and J. R. Murphy. 1988. Analysis of the diphtheria tox promoter by site-directed mutagenesis. J. Bacteriol. 170:59495952.
6. Boyd, J.,, M. Oza,, and J. R. Murphy. 1990. Molecular cloning and DNA sequence analysis of an iron dependent diphtheria tox regulatory element (dtxR) from Corynebacterium diphtheriae. Proc. Natl. Acad. Sci. USA 87:59685972.
7. Boyd, J.,, K. Hall,, and J. R. Murphy. 1992. Characterization of dtxR alleles from Corynebacterium diphtheriae strains PW8, 1030, and C7hm723. J. Bacteriol. 174:12681272.
8. Brown, J. G.,, B. D. Almond,, J. G. Naglich,, and L. Eidels. 1993. Hypersensitivity to diphtheria toxin by mouse cell expressing both diphtheria toxin receptor and CD9 antigen. Proc. Natl. Acad. Sci. USA 90:81848188.
9. Buck, G. A.,, R. E. Cross,, T. P. Wong,, J. Lorea,, and N. Groman. 1985. DNA relationships among some tox-bearing corynebacteriophages. Infect. Immun. 49:679684.
10. Ceredeño-Tárraga, A. M.,, A. Efstratiou,, L. G. Dover,, M. T. G. Holden,, M. Phallen,, S. D. Bentley,, G. S. Besra,, C. Churcher,, K. D. James,, A. De Zoysa,, T. Chillingsworth,, A. Cronin,, L. Dowd,, T. Feltwell,, N. Hamlin,, S. Holroyd,, K. Jagels,, S. Moule,, M. A. Quail,, E. Rabbinowitsch,, K. M. Rutherford,, N. R. Thomson,, L. Unwin,, S. Whitehead,, B. G. Barrell,, and J. Parkhill. 2003. The complete genome sequence and analysis of Corynebacterium diphtheriae NCTC13129. Nucleic Acids Res. 31:65166523.
11. Chen, C. S.,, A. White,, J. Love,, J. R. Murphy,, and D. Ringe. 2000. Methyl groups of thymine bases are important for nucleic acid recognition by DtxR. Biochemistry 39:1039710407.
12. Choe, S.,, M. J. Bennett,, G. Fugii,, P. M. G. Curmi,, K. A. Kantardjieff,, R. J. Collier,, and D. Eisenberg. 1992. The crystal structure of diphtheria toxin. Nature 357:216222.
13. Cole, S. T.,, R. Brosch,, J. Parkhill,, T. Garnier,, C. Churcher,, D. Harris,, S. V. Gordon,, K. Eiglmeier,, S. Gas,, C. E. BarryIII,, F. Tekaia,, K. Badcock,, D. Basham,, D. Brown,, T. Chillingworth,, R. Connor,, R. Davies,, K. Devlin,, T. Feltwell,, S. Gentles,, N. Hamlin,, S. Holroyd,, T. Hornsby,, K. Jagels,, and B. G. Barrell. 1998. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393:537544.
14. D’Aquino, J. A.,, and D. Ringe. 2003. Determinants of the Src homology domain 3-like fold. J. Bacteriol. 185:40814086.
15. Ding, X.,, H. Zeng,, N. Schiering,, D. Ringe,, and J. R. Murphy. 1966. Identification of the primary metal ion-activation sites of the diphtheria tox repressor by X-ray crystallography and site-directed mutagenesis. Nat. Struct. Biol. 3:382387.
16. Doukhan, L.,, M. Predich,, G. Nair,, O. Dussurget,, I. Manic-Mulec,, S. T. Cole,, D. R. Smith,, and I. Smith. 1995. Genomic organization of the mycobacterial sigma gene cluster. Gene 165:6770.
17. Drazin, R.,, J. Kandel,, and R. J. Collier. 1971. Structure and activity of diphtheria toxin. II. Attack by trypsin at a specific site within the intact toxin molecule. J. Biol. Chem. 246:15041510.
18. Foss, F. M.,, M. N. Saleh,, J. G. Krueger,, J. C. Nichols,, and J. R. Murphy. 1997. Diphtheria toxin fusion proteins. Curr. Top. Microbiol. Immunol. 234:6381.
19. Fourel, G.,, A. Phalipon,, and M. Kaczorek. 1989. Evidence for direct regulation of diphtheria toxin gene tran scription by an Fe2+-dependent DNA-binding repressor, DtoxR, in Corynebacterium diphtheriae. Infect. Immun. 57:32213225.
20. Gill, D. M. 1982. Bacterial toxins: a table of lethal amounts. Microbiol. Rev. 46:8694.
21. Gill, D. M.,, and A. M. Pappenheimer, Jr. 1971. Structure-activity relationships in diphtheria toxin. J. Biol. Chem. 246:14921495.
22. Glasfeld, A.,, E. Guedon,, J. D. Helmann,, and R. G. Brennan. 2003. Structure of the manganese-bound manganese transport regulator of Bacillus subtilis. Nat. Struct. Biol. 10:652657.
23. Greenfield, L.,, M. J. Bjorn,, G. Horn,, D. Fong,, G. A. Buck,, R. J. Collier,, and D. A. Kaplan. 1983. Nucleotide sequence of the structural gene for diphtheria toxin carried by corynebacteriophage β. Proc. Natl. Acad. Sci. USA 80:68536857.
24. Groman, N. B.,, and K. Judge. 1979. Effects of metal ions on diphtheria toxin production. Infect. Immun. 26:10651070.
25. Gubler, J.,, C. Huber-Schneider,, E. Gruner,, and M. Altwegg. 1998. An outbreak of nontoxigenic Corynebacterium diphtheriae infection: single bacterial clone causing invasive infection among Swiss drug users. Clin. Infect. Dis. 27:12951298.
26. Günter, K.,, C. Toupet,, and T. Schupp. 1993. Characterization of an iron-regulated promoter involved in desferrioxamine B synthesis in Streptomyces pilosus: repressor-binding site and homology to the diphtheria toxin gene promoter. J. Bacteriol. 175:32953302.
27. Günter-Seeboth, K.,, and T. Schupp. 1995. Cloning and sequence analysis of the Corynebacterium diphtheriae dtxR homologue from Streptomyces lividans and S. pilosus encoding a putative iron repressor. Gene 166:117119.
28. Hardham, J. M.,, L. V. Stamm,, S. F. Porcella,, J. G. Frye,, N. Y. Barnes,, J. K. Howell,, S. L. Mueller,, J. D. Radolf,, G. M. Weinstock,, and S. J. Norris. 1997. Identification and transcriptional analysis of a Treponema pallidum operon encoding a putative ABC transport system, an iron-activated repressor protein homolog, and a glycolytic pathway enzyme homolog. Gene 197:4764.
29. Hardy, I. R. B.,, S. Dittman,, and R. W. Sutter. 1996. Current situation and control strategies for resurgence of diphtheria in newly independent states of the former Soviet Union. Lancet 347:17391744.
30. Ho, V. T.,, D. Zahrieh,, E. Hochberg,, E. Micale,, J. Levin,, C. Reynolds,, S. Steckel,, C. Cutler,, D. C. Fisher,, S. J. Lee,, E. P. Alyea,, J. Ritz,, R. J. Soiffer,, and J. H. Antin. 2004. Safety and efficacy of denileukin diftitox in patients with steroid-refractory acute graft- versus-host disease after allogeneic hematopoietic stem cell transplantation. Blood 104:12241226.
31. Horsburgh, M. J.,, S. J. Wharton,, A. G. Cox,, E. Ingham,, S. Peacock,, and S. J. Foster. 2002. MntR modulates expression of the PerR regulon and superoxide resistance in Staphylococcus aureus through control of manganese uptake. Mol. Microbiol. 44:12691286.
32. Hu, H.-Y.,, P. D. Hunth,, J. R. Murphy,, and J. C. vander-Spek. 1998. The effects of helix breaking mutations in the diphtheria toxin transmembrane domain helix layers of the fusion toxin DAB389IL-2. Protein Eng. 11:101107.
33. Iwamoto, R.,, H. Senoh,, Y. Okada,, and E. Mekada. 1991. An antibody that inhibits the binding of diphtheria toxin to cells revealed the association of a 27-kDa membrane protein with the diphtheria toxin receptor. J. Biol. Chem. 266:2046320469.
34. Kaczorek, M.,, F. Delpyyroux,, N. Chenciner,, R. E. Streek,, J. R. Murphy,, P. Boquet,, and P. Tiollais. 1983. Nucleotide sequence and expression in Escherichia coli of the CRM228 diphtheria toxin gene. Science 221:855858.
35. Kanei, C.,, T. Uchida,, and M. Yoneda. 1977. Isolation from Corynebacterium diphtheriae C7(β) of bacterial mutants that produce toxin in medium containing excess iron. Infect. Immun. 18:203209.
36. Kitten, T.,, C. L. Munro,, S. M. Michalek,, and F. L. Macrina. 2000. Genetic characterization of a Streptococcus mutans LraI family operon and role in virulence. Infect. Immun. 68:44414451.
37. Krafft, A. E.,, S. P. Tai,, C. Coker,, and R. K. Holmes. 1992. Transcription analysis and nucleotide sequence of tox promoter/operator mutants of corynebacteriophage beta. Microb. Pathog. 13:8592.
38. Lawson, C. L.,, and J. Carey. 1993. Tandem binding in crystals of a trp repressor/operator half site complex. Nature 366:178182.
39. Lee, J. H.,, T. Wang,, K. Ault,, J. Liu,, M. P. Schmitt,, and R. K. Holmes. 1997. Identification and characterization of three new promoter/operators from Corynebacterium diphtheriae that are regulated by the diphtheria toxin repressor (DtxR) and iron. Infect. Immun. 65:42734280.
40. Lieser, S. A.,, T. C. Davis,, J. D. Helmann,, and S. M. Cohen. 2003. DNA-binding and oligomerization studies of the manganese(II) metalloregulatory protein MntR from Bacillus subtilis. Biochemistry 42:1263412642.
41. Love, J. F.,, and J. R. Murphy. 2002. Design and development of a novel genetic probe for the analysis of repressor-operator interactions. J. Microbiol. Methods 51:6372.
42. Love, J. F.,, J. C. vanderSpek,, and J. R. Murphy. 2003. The src homology 3-like domain of the diphtheria toxin repressor (DtxR) modulates repressor activation through interaction with the ancillary metal ion-binding site. J. Bacteriol. 185:22512258.
43. Love, J. F.,, J. C. vanderSpek,, V. Marin,, L. Guerrero,, T. M. Logan,, and J. R. Murphy. 2004. Genetic and biophysical studies of diphtheria toxin repressor and the hyperactive mutant DtxR(E175K) support a multistep model for activation. Proc. Natl. Acad. Sci. USA 101:25062511.
44. Low, Y. L.,, N. S. Jakubovics,, J. C. Flatman,, H. F. Jenkinson,, and A. W. Smith. 2003. Manganese-dependent regulation of the endocarditis-associated virulence factor EfaA of Enterococcus faecalis. J. Med. Microbiol. 52:113119.
45. Lund, R. A. 1995. The role of molecular chaparones in vivo. Essays Biochem. 29:113129.
46. Manabe, Y. C.,, B. J. Saviola,, L. Sun,, J. R. Murphy,, and W. R. Bishai. 1999. Attenuation of virulence in Mycobacterium tuberculosis expressing a constitutively active iron repressor. Proc. Natl. Acad. Sci. USA 96:1284412848.
47. Maurice, J. 1995. Russian chaos breeds diphtheria outbreak. Science 167:14161417.
48. McQuillan, G. M.,, D. Kruszon-Moran,, A. Deforest,, S. Y. Chu,, and M. Wharton. 2002. Serologic immunity to diphtheria and tetanus in the United States. Ann. Intern. Med. 136:660666.
49. Mitamura, T.,, R. Iwamoto,, T. Umata,, T. Yomo,, I. Urabe,, M. Tsuneoka,, and E. Mekada. 1992. The 27-kD diphtheria toxin receptor-associated protein (DRAP27) from Vero cells is the monkey homologue of human CD9 antigen: expression of DRAP27 elevates the number of diphtheria toxin receptors on toxin-sensitive cells. J. Cell Biol. 118:13891399.
50. Moreira, L. O.,, A. F. B. Andrade,, M. D. Vale,, S. M. S. Souza,, R. Hirata, Jr.,, L. M. O. B. Asad,, N. R. Asad,, L. H. Monteiro-Leal,, J. O. Previato,, and A. L. Mattos-Guaraldi. 2003. Effects of iron limitation on adherence and cell surface carbohydrates of Corynebacterium diphtheriae strains. Appl. Environ. Microbiol. 69:59075913.
51. Moya, M.,, A. Dautry-Versat,, B. Goud,, D. Louvard,, and P. Boquet. 1985. Inhibition of coated-pit formation in Hep2 cells blocks the cytotoxicity of diphtheria toxin but not ricin toxin. J. Cell Biol. 101:548559.
52. Murphy, J. R.,, and P. Bacha,. 1979. Studies of the regulation of diphtheria toxin production, p. 181186. In D. Schlessinger (ed.), Microbiology1979. American Society for Microbiology, Washington, D.C.
53. Murphy, J. R.,, A. M. Pappenheimer, Jr.,, and S. Tayart de Borms. 1974. Synthesis of diphtheria tox gene products in Escherichia coli extracts. Proc. Natl. Acad. Sci. USA 71:1115.
54. Murphy, J. R.,, J. Skiver,, and G. McBride. 1976. Isolation and partial characterization of a corynebacteriophage tox operator constitutive-like mutant lysogen of Corynebacterium diphtheriae. J. Virol. 18:235244.
55. Murphy, J. R.,, W. Bishai,, M. Borowski,, A. Miyanohara,, J. Boyd,, and S. Nagle. 1986. Genetic construction, expression, and melanoma selective cytotoxicity of a diphtheria toxin α-melanocyte stimulating hormone fusion protein. Proc. Natl. Acad. Sci. USA 83:82588262.
56. Murphy, J. R.,, and J. C. vanderSpek. 1995. Targeting diphtheria toxin to growth factor receptors. Semin. Cancer Biol. 6:259267.
57. Naglich, J. G.,, J. E. Matherall,, D. W. Russell,, and L. Eidels. 1992. Expression cloning of a diphtheria toxin receptor: identity with a heparin-binding EGF-like growth factor precursor. Cell 69:10511061.
58. Nakamura, Y.,, Y. Nishio,, K. Ikeo,, and T. Gojobori. 2003. The genome stability in Corynebacterium species due to lack of the recombinational repair system. Gene 317:149155.
59. Nakao, H.,, I. K. Mazurova,, T. Glushkevich,, and T. Popovic. 1997. Analysis of heterogeneity of Corynebacterium diphtheriae toxin gene, tox, and its regulatory element, dtxR, by direct sequencing. Res. Microbiol. 148: 4554.
60. Nakao, H.,, J. M. Pruckler,, I. K. Mazurova,, O. V. Narvskaia,, T. Glushkevich,, V. F. Marijevski,, A. N. Kravetz,, B. I. Fields,, I. K. Wachsmuth,, and T. Popovic. 1996. Heterogeneity of diphtheria toxin gene, tox, and its regulatory element, dtxR, in Corynebacterium diphtheriae strains causing epidemic diphtheria in Russia and Ukraine. J. Clin. Microbiol. 34:17111716.
61. Oguiza, J. A.,, X. Tao,, A. T. Marcos,, J. F. Martin,, and J. R. Murphy. 1995. Molecular cloning and characterization of the Corynebacterium diphtheriae dtxR homolog from Brevibacterium lactofermentum. J. Bacteriol. 177:465467.
62. Pappenheimer, A. M., Jr.,, and S. J. Johnson. 1936. Studies in diphtheria toxin production. I: The effects of iron and copper. Br. J. Exp. Pathol. 17:335341.
63. Pappenheimer, A. M., Jr. 1977. Diphtheria toxin. Annu. Rev. Biochem. 46:6994.
64. Pappenheimer, A. M., Jr. 1980. Diphtheria: studies on the biology of an infectious disease, p. 4573. In The Harvey Lectures, series 76. Academic Press, Inc., New York, N.Y.
65. Pappenheimer, A. M., Jr.,, and J. R. Murphy. 1983. Studies on the molecular epidemiology of diphtheria. Lancet ii:923926.
66. Patzer, S. I.,, and K. Hantke. 2001. Dual repression by Fe2+-Fur and Mn2+-MntR of the mntH gene, encoding an NRAMP-like Mn2+ transporter in Escherichia coli. J. Bacteriol. 183:48064813.
67. Pohl, E.,, X. Qiu,, L. M. Must,, R. K. Holmes,, and W. G. J. Hol. 1997. Comparison of high-resolution structures of the diphtheria toxin repressor in complex with cobalt and zinc at the cation-anion binding site. Protein Sci. 6:11141118.
68. Pohl, E.,, R. K. Holmes,, and W. G. J. Hol. 1998. Motion of the DNA-binding domain with respect to the core of the diphtheria toxin repressor (DtxR) revealed in the crystal structures of apo- and holo-DtxR. J. Biol. Chem. 273:2242022427.
69. Pohl, E.,, R. K. Holmes,, and W. G. J. Hol. 1999. Crystal structure of a cobalt-activated diphtheria toxin repressor-DNA complex reveals a metal-binding SH3-like domain. J. Mol. Biol. 292:653667.
70. Pohl, E.,, J. Goranson-Siekierke,, M. K. Choi,, T. Roosild,, R. K. Holmes,, and W. G. J. Hol. 2001. Structures of three diphtheria toxin repressor (DxtR) variants with decreased repressor activity. Acta Crystallogr. D Biol. Crystallogr. 57:619627.
71. Popovic, T.,, C. Kim,, J. Reiss,, M. Reeves,, H. Nakao,, and A. Golaz. 1999. Use of molecular subtyping to document long-term persistence of Corynebacterium diphtheriae in South Dakota. J. Clin. Microbiol. 37:10921099.
72. Posy, J. E.,, J. M. Hardham,, S. J. Norris,, and F. C. Gherardini. 1999. Characterization of a manganese-dependent regulatory protein, TroR, from Treponema pallidum. Proc. Natl. Acad. Sci. USA 96:1088710892.
73. Qian, Y.,, J. H. Lee,, and R. K. Holmes. 2002. Identification of a DtxR-regulated operon that is essential for siderophore-dependent iron uptake in Corynebacterium diphtheriae. J. Bacteriol. 184:48464865.
74. Qiu, X.,, C. L. Verlinde,, S. Zhang,, M. P. Schmitt,, R. K. Holmes,, and W. G. J. Hol. 1995. Three-dimensional structure of the diphtheria toxin repressor in complex with divalent cation co-repressors. Structure 3:87100.
75. Qiu, X.,, E. Pohl,, R. K. Holmes,, and W. G. J. Hol. 1996. High-resolution structure of the diphtheria toxin repressor complexed with cobalt and manganese reveals an SH3-like third domain and suggests a possible role of phosphate as co-repressor. Biochemistry 35:1229212302.
76. Que, Q.,, and J. D. Helmann. 2000. Manganese homeostasis in Bacillus subtilis is regulated by MntR, a bifunctional regulator related to the diphtheria toxin repressor family of proteins. Mol. Microbiol. 35:14541468.
77. Ramon, G. 1923. Sur la concentration du serum antidiphtherique et l’isoletment de la antitoxine. C. R. Seances Soc. Biol. Fil. 88:167168.
78. Ratti, G.,, R. Rappuoli,, and G. Giannini. 1983. The complete nucleotide sequence of the gene coding for diphtheria toxin in the corynephage omega (tox+) genome. Nucleic Acids Res. 11:65896595.
79. Ratts, R.,, H. Zeng,, E. A. Berg,, C. Blue,, M. E. McComb,, C. E. Costello,, J. C. vanderSpek,, and J. R. Murphy. 2003. The cytosolic entry of diphtheria toxin catalytic domain requires a host cell cytosolic translocation factor complex. J. Cell Biol. 160:11391150.
80. Ryser, H.-J.,, R. Mandel,, and F. Ghani. 1991. Cell surface sulfhydryls are required for the cytotoxicity of diphtheria toxin but not ricin toxin in Chinese hamster ovary cells. J. Biol. Chem. 266:1843918442.
81. Saragea, A.,, P. Maximescu,, and E. Meitert. 1979. Corynebacterium diphtheriae: microbiological methods used in clinical and epidemiological investigations. Methods Microbiol. 13:61176.
82. Schiering, N.,, X. Tao,, H. Zeng,, J. R. Murphy,, G. A. Petsko,, and D. Ringe. 1995. Structures of the apo- and the metal ion-activated forms of the diphtheria tox repressor from Corynebacterium diphtheriae. Proc. Natl. Acad. Sci. USA 92:98439850.
83. Schmitt, M. P.,, and R. K. Holmes. 1991. Characterization of a defective diphtheria toxin repressor (dtxR) allele and analysis of dtxR transcription in wild-type and mutant strains of Corynebacterium diphtheriae. Infect. Immun. 59:39033908.
84. Schmitt, M. P.,, and R. K. Holmes. 1994. Cloning, sequence, and footprint analysis of two promoter/operators from Corynebacterium diphtheriae that are regulated by the diphtheria toxin repressor (DtxR) and iron. J. Bacteriol. 176:11411149.
85. Schmitt, M. P.,, M. Predich,, L. Doukhan,, I. Smith,, and R. K. Holmes. 1995. Characterization of an iron-dependent regulatory protein (IdeR) of Mycobacterium tuberculosis as a functional homolog of the diphtheria toxin repressor (DtxR) from Corynebacterium diphtheriae. Infect. Immun. 63:42844289.
86. Schmitt, M. P. 1997. Transcription of the Corynebacterium diphtheriae hmuO gene is regulated by iron and heme. Infect. Immun. 65:46344641.
87. Schmitt, M. P. 2002. Analysis of a DtxR-like metalloregulatory protein, MntR, from Corynebacterium diphtheriae that controls expression of an ABC metal transporter by an Mn2+-dependent mechanism. J. Bacteriol. 184:68826892.
88. Skogen, V.,, V. V. Cherkasova,, N. Maksimova,, C. K. Marston,, H. Sjursen,, M. W. Reeves,, O. Olsvik,, and T. Popovic. 2002. Molecular characterization of Corynebacterium diphtheriae isolates, Russia, 1957-1987. Emerg. Infect. Dis. 8:516518.
89. Smith, W. P.,, P. C. Tai,, J. R. Murphy,, and B. D. Davis. 1980. A precursor in the cotranslational secretion of diphtheria toxin. J. Bacteriol. 141:184189.
90. Spiering, M. M.,, D. Ringe,, J. R. Murphy,, and M. A. Marletta. 2003. Metal ion stoichiometry and functional studies of the diphtheria toxin repressor. Proc. Natl. Acad. Sci. USA 100:38083813.
91.. Sun, L.,, and J. R. Murphy. Unpublished data.
92. Sun, L.,, J. C. vanderSpek,, and J. R. Murphy. 1998. Isolation and characterization of iron-independent positive dominant mutants of the diphtheria toxin repressor DtxR. Proc. Natl. Acad. Sci. USA 95:1498514990.
93. Tao, X.,, J. Boyd,, and J. R. Murphy. 1992. Specific binding of the diphtheria tox regulatory element DtxR to the tox operator requires divalent cations and a 9-base-pair interrupted palindromic sequence. Proc. Natl. Acad. Sci. USA 89:58975901.
94. Tao, X.,, and J. R. Murphy. 1992. Binding of the metalloregulatory protein DtxR to the diphtheria tox operator requires a divalent heavy metal ion and protects the palindromic sequence from DNase I digestion. J. Biol. Chem. 267:2176121764.
95. Tao, X.,, and J. R. Murphy. 1993. Cysteine-102 is positioned in the metal binding activation site of the Corynebacterium diphtheriae regulatory element DtxR. Proc. Natl. Acad. Sci. USA 90:85248528.
96. Tao, X.,, and J. R. Murphy. 1994. Determination of the DtxR consensus binding site by in vitro affinity selection. Proc. Natl. Acad. Sci. USA 91:96469650.
97. Tao, X.,, H. Zeng,, and J. R. Murphy. 1995. Heavy metal ion activation of the diphtheria tox repressor (DtxR) results in the formation of stable homodimers. Proc. Natl. Acad. Sci. USA 92:68036807.
98. Ton-Than, H.,, and O. Schneewind. 2003. Assembly of pili on the surface of Corynebacterium diphtheriae. Mol. Microbiol. 50:14291438.
99. Touate, D.,, M. Jacques,, B. Tardat,, L. Bouchard,, and S. Despied. 1995. Lethal oxidative damage and mutagenesis are generated by iron in δfur mutants of Escherichia coli: protective role of superoxide dismutase. J. Bacteriol. 177:23052314.
100. Twigg, P. D.,, G. P. Wylie,, G. Wang,, D. L. D. Caspar,, J. R. Murphy,, and T. M. Logan. 1999. Expression and assignment of the 1H, 15N, and 13C resonances of the Cterminal domain of the diphtheria toxin repressor. J. Biomol. NMR 13:197198.
101. Twigg, P. D.,, G. Parthasarathy,, L. Guerrero,, T. M. Logan,, and D. L. Caspar. 2001. Disordered to ordered folding in the regulation of diphtheria toxin repressor activity. Proc. Natl. Acad. Sci. USA 98:1125911264.
102. Uchida, T.,, D. M. Gill,, and A. M. Pappenheimer, Jr. 1971. Mutation in the structural gene for diphtheria toxin carried by temperate phage β. Nature New Biol. 233:811.
103. Vitek, C. R.,, and M. Wharton. 1998. Diphtheria in the former Soviet Union: reemergence of a pandemic disease. Emerg. Infect. Dis. 4:539550.
104. Wang, G.,, G. P. Wylie,, P. D. Twigg,, D. L. D. Caspar,, J. R. Murphy,, and T. M. Logan. 1999. Solution structure and peptide binding studies of the C-terminal Src homology 3-like domain of the diphtheria toxin repressor protein. Proc. Natl. Acad. Sci. USA 96:61196124.
105. Wang, Z.,, M. P. Schmitt,, and R. K. Holmes. 1994. Characterization of mutations that inactivate the diphtheria toxin repressor. Infect. Immun. 62:16001608.
106. Welkos, S. L.,, and R. K. Holmes. 1981. Regulation of toxinogenesis in Corynebacterium diphtheriae. I. Mutations in bacteriophage β that alter the effect of iron on toxin production. J. Virol. 37:936945.
107. White, A.,, X. Ding,, J. R. Murphy,, and D. Ringe. 1998. Structure of metal ion-activated diphtheria toxin repressor/tox operator complex. Nature 394:502506.
108. Yamaizumi, M.,, E. Mekada,, T. Uchida,, and Y. Okada. 1978. One molecule of diphtheria toxin fragment A introduced into a cell can kill the cell. Cell 15:245250.
109. Zeng, H.,, and J. R. Murphy. Unpublished data.
110. Zhang, H.,, D. Zhao,, M. Revington,, W. Lee,, X. Jia,, C. Arrowsmith,, and O. Jardetzky. 1994. The solution structures of the trp repressor-operator DNA complex. J. Mol. Biol. 238:592614.
111. Zucker, D. R.,, and J. R. Murphy. 1984. Monoclonal antibody analysis of diphtheria toxin. I. Localization of epitopes and neutralization of cytotoxicity. Mol. Immunol. 21:785793.

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error