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

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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

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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
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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
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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
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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
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