Disease relevance of dtxR

• Diphtheria toxin repressor (DtxR) regulates the expression of iron-sensitive genes in Corynebacterium diphtheriae, including the diphtheria toxin gene [1].
• In addition, we show that expression of the toxPO-lacZ fusion is not affected by the E. coli iron-regulatory protein Fur and that the dtxR protein does not inhibit expression of fur-regulated outer-membrane proteins [2].
• Cloned dtxR was expressed in Escherichia coli from the phage T7 gene 10 promoter, and DtxR was purified [3].
• Here, we report the cloning and sequencing of the putative Streptomyces iron repressor gene, homologous to dtxR of C. diphtheriae [4].
• A homolog of the Corynebacterium diphtheriae dtxR gene was isolated from Brevibacterium lactofermentum [5].

High impact information on dtxR

• Structure of the metal-ion-activated diphtheria toxin repressor/tox operator complex [6].
• The diphtheria toxin repressor (DtxR) is a metal ion-activated transcriptional regulator that has been linked to the virulence of Corynebacterium diphtheriae [7].
• We also demonstrate that the C-terminal src homology 3 (SH3)-like domain of DtxR functions to modulate repressor activity by (i) binding to the polyprolyl tether region between the N- and C-terminal domains, and (ii) destabilizing the ancillary binding site, leading to full inactivation of the repressor [8].
• Gel electrophoretic mobility-shift assays show that Fe(2+) and not Fe(3+) activates DtxR for DNA binding [9].
• Metal binding lowers the dimerization K(d) of DtxR from low micromolar to 33 nM [9].

Chemical compound and disease context of dtxR

• Manganese homeostasis in Bacillus subtilis is regulated by MntR, a bifunctional regulator related to the diphtheria toxin repressor family of proteins [10].
• The diphtheria toxin repressor (DtxR) uses Fe(2+) as a corepressor and inhibits transcription from iron-regulated promoters (IRPs) in Corynebacterium diphtheriae [11].

Biological context of dtxR

• DtxR is a two-domain protein that contains two structurally and functionally distinct metal binding sites [12].
• The diphtheria toxin repressor (DtxR) is an Fe(II)-activated transcriptional regulator of iron homeostatic and virulence genes in Corynebacterium diphtheriae [12].
• DNA sequence analysis of dtxR has shown that the M(r) 25,316 regulatory protein contains a single cysteine residue at position 102 [13].
• Partial diploid analysis of strains carrying both native dtxR and alleles encoding either SAD2 or SAD3 demonstrate that these iron-independent mutants possess a positive dominant phenotype in the regulation of beta-galactosidase expression from a diphtheria tox promoter/operator-lacZ transcriptional fusion [14].
• Expression of the cloned dtxR determinant did not affect the phenotype of C. diphtheriae C7(beta) [15].

Associations of dtxR with chemical compounds

• Together, the structural and biophysical studies suggest that the proline-rich peptide segment of DtxR functions as a switch that modulates the activation of repressor activity [1].
• The dtxR allele from C7(beta)hm723 contained a single-base change located 140 nucleotides from the 5' start of the gene, which resulted in replacement of arginine in the wild-type sequence by histidine in the mutant protein [16].
• In contrast, the presence of sodium dodecyl sulfate was the only factor tested that conclusively affects the number of transcripts initiated in the sigB-dtxR intergenic region [17].
• While DtxR mediates the iron-dependent repression of iron uptake, we demonstrate that yqhN (herein renamed mntR) encodes a manganese modulated regulator of manganese transport [10].
• Hydroxyl radical footprinting experiments indicated that DtxR binds symmetrically about the dyad axis of the tox operator [18].

Regulatory relationships of dtxR

• A DNA fragment carrying dtxR repressed expression of a tox-lacZ gene fusion in Escherichia coli DH5 alpha in a high-iron environment but not under low-iron conditions [15].

Other interactions of dtxR

• Additionally, we provided evidence for the existence of transcripts that contain sigB, dtxR, and galE [17].
• Strain HC3 was found to have a chain-terminating mutation in dtxR in addition to a missense mutation in its irp6B allele [11].

Analytical, diagnostic and therapeutic context of dtxR

• The molecular cloning and sequence analysis of dtxR was recently described [19].
• DNA fragments carrying dtxR were cloned into pCM2.6, and the hybrid shuttle plasmids were transformed by electroporation into wild-type C. diphtheriae C7(beta) and the regulatory mutant C7(beta)hm723, which produces toxin and siderophore constitutively under high-iron conditions [15].
• PCR amplification and sequence analysis of the dtxR genes revealed four variants of the predicted DtxR protein among the nontoxigenic strains isolated in the United Kingdom [20].
• A total of 26 nontoxigenic C. diphtheriae strains isolated in the United Kingdom during 1995 and 4 nontoxigenic strains isolated in other countries were analyzed by PCR and direct sequencing to determine the presence and intactness of the dtxR genes [20].
• First, global gene expression of a dtxR deletion mutant was compared with that of the wild type using DNA microarrays [21].

References