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PubMed2002

Formation of the stoichiometric complex of EnvZ, a histidine kinase, with its response regulator, OmpR.

EnvZ, a histidine kinase, and its cognate response regulator OmpR of Escherichia coli are responsible for adaptation to external osmotic changes by regulating the levels of the outer membrane porin proteins, OmpF and OmpC. The osmosensor, EnvZ, has dual enzymatic functions with OmpR kinase and OmpR-P phosphatase. Here, we demonstrate that the cytoplasmic kinase domain of EnvZ (EnvZc) and OmpR are able to form a 1:1 complex detected by native PAGE. This indicates that two OmpR molecules can bind to one EnvZc dimer. As this 1:1 EnvZc/OmpR complex is formed even in the presence of a large excess of EnvZc, OmpR binding to EnvZc is co-operative. The complex formation is also observed between EnvZc and phosphorylated OmpR for the phosphatase reaction. OmpR-P bound to EnvZc was readily released upon the addition of OmpR, indicating that OmpR and OmpR-P can compete for the binding to EnvZ. On the basis of these results, a model is discussed to explain how cellular OmpR-P concentrations are regulated in response to medium osmolarity.

Adenosine Triphosphate↗

PubMed2006

Age-related differences in response regulation as revealed by functional MRI.

This fMRI study studied age-related differences in neural activities during response regulation. Twenty-one male participants from two age groups, a younger group and an older group (mean ages: 29.9 and 65.2 years, respectively), were scanned while performing a task with response compatibility manipulation. They were presented with a sequence of arrowheads that pointed either upward or downward. In the "Response Compatible" condition, they were required to press an up or a down button consistent with the direction of the arrowhead. In the "Response Incompatible" condition, they were required to press the button opposite to the arrowhead direction so that an upward arrow should elicit a down response, and vice versa. Findings showed age-related differences in response regulation in several brain regions, including the right frontal, the right cingulate, and the left inferior parietal cortexes. The findings suggested a higher level of neural activity in the right prefrontal and left inferior parietal regions during response regulation for the older adults than for the younger adults.

Adult↗

PubMed2002

The FxRxHrS motif: a conserved region essential for DNA binding of the VirR response regulator from Clostridium perfringens.

The VirSR two-component signal transduction pathway regulates virulence and toxin production in Clostridium perfringens, the causative agent of gas gangrene. The response regulator, VirR, binds to repeat sequences located upstream of the promoter and is directly responsible for the transcriptional activation of pfoA, the structural gene for the cholesterol-dependent cytolysin, perfringolysin O. Comparative sequence analysis of the 236 amino acid residue VirR protein revealed a two-domain structure: a typical N-terminal response regulator domain and an uncharacterised C-terminal domain. Database searching revealed that over 40 other proteins, many of which appeared to be response regulators or transcriptional activators, had homology with the VirR C-terminal domain (VirRc). Multiple sequence alignment of this VirRc family revealed a highly conserved region that was designated the FxRxHrS motif. By deletion analysis this motif was shown to be essential for the functional integrity of the VirR protein. Alanine scanning mutagenesis and subsequent phenotypic analysis indicated that conserved residues located within the motif were required for activity. These residues extended from L179 to N194. More detailed site-directed mutagenesis showed that amino acid residues R186, H188 and S190 were essential for activity since even conservative substitutions in these positions resulted in non-functional proteins. Three of the mutant proteins, R186K, S190A and S190C, were purified and shown by in vitro gel shift analysis to be unable to bind to the specific target DNA with the same efficiency as the wild-type protein. These data reveal for the first time that VirRc functions as a DNA binding domain in which the highly conserved FxRxHrS motif has a functional role. These studies have important implications for this new family of transcriptional factors since they imply that the conserved FxRxHrS motif may be involved in DNA binding in all of these proteins, irrespective of their biological role.

Amino Acid Motifs↗

PubMed1999

Heme is an effector molecule for iron-dependent degradation of the bacterial iron response regulator (Irr) protein.

The bacterial iron response regulator (Irr) protein mediates iron-dependent regulation of heme biosynthesis. Pulse-chase and immunoprecipitation experiments showed that Irr degraded in response to 6 microM iron with a half-life of approximately 30 min and that this regulated stability was the principal determinant of control by iron. Irr contains a heme regulatory motif (HRM) near its amino terminus. A role for heme in regulation was implicated by the retention of Irr in heme synthesis mutants in the presence of iron. Addition of heme to low iron (0.3 microM) cultures was sufficient for the disappearance of Irr in cells of the wild-type and heme mutant strains. Spectral and binding analyses of purified recombinant Irr showed that the protein bound heme with high affinity and caused a blue shift in the absorption spectrum of heme to a shorter wavelength. A Cys(29) --> Ala substitution within the HRM of Irr (IrrC29A) abrogated both high affinity binding to heme and the spectral blue shift. In vivo turnover experiments showed that, unlike wild-type Irr, IrrC29A was stable in the presence of iron. We conclude that iron-dependent degradation of Irr involves direct binding of heme to the protein at the HRM. The findings implicate a regulatory role for heme in protein degradation and provide direct evidence for a functional HRM in a prokaryote.

Bacterial Proteins↗

PubMed2006

The maize transfer cell-specific type-A response regulator ZmTCRR-1 appears to be involved in intercellular signalling.

Response regulators are signal-transduction molecules present in bacteria, yeast and plants, acting as relays for environmental challenges. This paper reports the characterization of a Zea mays gene, ZmTCRR-1, that codes for a member of the type-A response regulator class of proteins. The gene was found to be expressed exclusively in the endosperm transfer-cell layer 8-14 days after pollination, when transfer-cell differentiation is most active. The promoter of ZmTCRR-1 was strongly transactivated in heterologous systems by the transfer cell-specific transcription factor ZmMRP-1. The ZmTCRR-1 protein was detected not only in the transfer-cell layer, but also in the conductive tissue deep inside the endosperm, where there is no transcription of the gene. This suggests that two-component systems might be involved in intercellular signal transmission, in contrast to the generally held belief that these systems are involved only in cell-autonomous pathways.

Amino Acid Sequence↗

PubMed2005

Construction and characterization of Listeria monocytogenes mutants with in-frame deletions in the response regulator genes identified in the genome sequence.

Two-component systems are widely distributed in prokaryotes where they control gene expression in response to diverse stimuli. To study the role of the sixteen putative two-component systems of Listeria monocytogenes systematically, in frame deletions were introduced into 15 out of the 16 response regulator genes and the resulting mutants were characterized. With one exception the deletion of the individual response regulator genes has only minor effects on in vitro and in vivo growth of the bacteria. The mutant carrying a deletion in the ortholog of the Bacillus subtilis response regulator gene degU showed a clearly reduced virulence in mice, indicating that DegU is involved in the regulation of virulence-associated genes.

Animals↗

PubMed1996

The response regulator SprE controls the stability of RpoS.

In Escherichia coli, the sigma factor, RpoS, is a central regulator in stationary-phase cells. We have identified a gene, sprE (stationary-phase regulator), as essential for the negative regulation of rpoS expression. SprE negatively regulates the rpoS gene product at the level of protein stability, perhaps in response to nutrient availability. The ability of SprE to destabilize RpoS is dependent on the ClpX/ClpP protease. Based on homology, SprE is a member of the response regulator family of proteins. SprE is the first response regulator identified that is implicated in the control of protein stability. Moreover, SprE is the first reported protein that appears to regulate rpoS in response to a specific environmental parameter.

ATPases Associated with Diverse Cellular Activitie↗

PubMed1998

Response regulators implicated in His-to-Asp phosphotransfer signaling in Arabidopsis.

The His to Asp phosphotransfer signal transduction mechanism involves three common signaling domains: the transmitter (or His-kinase), the receiver, and the histidine-containing phototransfer (HPt) domain. Typically, a sensor kinase has a His-kinase domain and a response regulator has a receiver domain containing a phosphoaccepting aspartate, whereas a histidine-containing phototransfer domain serves as a mediator of the histidine-to-aspartate phosphotransfer. This signal transduction mechanism was thought to be restricted to prokaryotes. However, many examples have been discovered in diverse eukaryotic species including higher plants. In Arabidopsis, three sensor kinases have been characterized, namely, ETR1, ERS, and CKI1, which were suggested to be involved in ethylene- and cytokinin-dependent signal transduction pathways, respectively. To date, no response regulator has been discovered in higher plants. We identify five distinct Arabidopsis response regulator genes, each encoding a protein containing a receiver-like domain. In vivo and in vitro evidence that ARRs can function as phosphoaccepting response regulators was obtained by employing the Escherichia coli His-Asp phosphotransfer signaling system.

Amino Acid Sequence↗

PubMed2001

A method for identification of inhibitors of the phosphorylation reactions of bacterial response regulator proteins using (31)P nuclear magnetic resonance spectroscopy.

Bacterial response regulators are attractive targets for antibacterial drug development, yet random screening against these targets has failed as yet to identify chemicals that constitute viable leads. Alternative methods to provide leads for drug development based on identification and optimization of low affinity ligands from NMR screens have been described. However, leads from these processes still require verification in a bioassay, which is often problematic if compounds have unfavorable optical and solubility properties. A simple method, based on using NMR to observe the activity of the target, is described. It has the advantages of being able to characterize both low affinity leads and a wider selection of compounds in a structure activity relationships series, without the problems affecting a fluorescence assay. In this example we use (31)P to monitor the turnover of a bacterial response regulator, but the generic approach could be applied to other nuclei and thus a range of biological systems.

Anti-Bacterial Agents↗

PubMed1999

Regulated interactions between partner and non-partner sensors and response regulators that control glycopeptide resistance gene expression in enterococci.

Transcription of the vanA and vanB glycopeptide resistance gene clusters is regulated by the VanRS and VanRBSB two-component regulatory systems, respectively. Histidine to glutamine substitutions were introduced at positions 164 of VanS and 233 of VanSB to prevent autophosphorylation of the sensor kinases and transfer of the phosphate groups to the VanR and VanRB response regulators. VanSH164Q and VanSBH233Q abolished activation of VanR and VanRB by host kinases. The phosphatase activity of VanSBH233Q was negatively modulated by vancomycin whereas VanSH164Q prevented transcription of the resistance genes under all growth conditions. Cross-talk was detected between VanRB and VanS in a vanSB null mutant. VanR is required for activation of promoters PR and PH allowing transcription of the regulatory (vanRS) and resistance (vanHAXYZ) genes, respectively. Under non-inducing conditions, activation of VanR by cross-talk was blocked by the presence of a multicopy plasmid carrying PH. Presence of the high-affinity VanR-binding sites of the regulatory region of PH on the multicopy vector probably sequestered VanR, thereby preventing autoactivation of the PR promoter. Under such circumstances, stimulation of the host kinase by glycopeptides or moenomycin was required for expression of the resistance genes.

Anti-Bacterial Agents↗

PubMed2000

An imperfect inverted repeat is critical for DNA binding of the response regulator RegR of Bradyrhizobium japonicum.

RegR is the response regulator of the RegSR two-component regulatory system in Bradyrhizobium japonicum. The only target known so far is the fixR-nifA operon, encoding the redox-responsive transcription factor NifA, which activates many genes required for symbiotic nitrogen fixation in soybean nodules. In previous in vivo studies, we identified a 32 bp upstream activating sequence located around position -68, which is essential for RegR-dependent expression of the fixR-nifA operon. Here, we used an in vitro binding-site selection assay (SELEX) to more precisely define the DNA-binding specificity of RegR. The selected sequences comprised an imperfect inverted repeat (GCGGC-N(5)-GTCGC) which is highly similar to an imperfect inverted repeat in the fixR UAS (GCGAC-N(5)-GACGC). In a parallel approach, band-shift experiments were performed with oligonucleotides comprising defined point or deletion mutations in the fixR UAS. This led to the identification of 11 critical nucleotides within a 17 bp minimal RegR binding site centered at position -64 upstream of the fixR-nifA transcription start site. Notably, all 11 critical nucleotides were located either within the half sites of the inverted repeat (four nucleotides in each half site) or in the 5 bp spacer that separates the half sites (three nucleotides). Based on these results, we defined a DNA motif comprising those nucleotides that are critical for RegR binding (RegR box; 5'-GNG(A)(G)C(A)(G)TTNNGNCGC-3'). A comparison of the RegR box with functional binding sites of the RegR-like regulator RegA of Rhodobacter capsulatus revealed considerable similarities. Thus, the RegR box may assist in the identification of new RegR target genes not only in B.japonicum but also in other alpha-proteobacteria possessing RegR-like response regulators.

Bacterial Proteins↗

PubMed2006

Two-component response regulators Ssk1p and Skn7p additively regulate high-osmolarity adaptation and fungicide sensitivity in Cochliobolus heterostrophus.

Filamentous ascomycetous fungi possess many histidine kinases and two conserved response regulators, Ssk1p and Skn7p, in their two-component signaling systems. We previously reported that the fungus unique group III histidine kinase regulates high-osmolarity adaptation and iprodione/fludioxonil fungicide sensitivity by controlling the phosphorylation of Hog1-type mitogen-activated protein kinase (MAPK) in filamentous ascomycetes. Here, we have characterized the response regulator genes ChSsk1 and ChSkn7 in the southern corn leaf blight fungus Cochliobolus heterostrophus. Both ChSsk1- and ChSkn7-disrupted mutants showed little sensitivity to high-osmolarity stress and moderate resistance to the iprodione/fludioxonil fungicides. The phosphorylation of Hog1-type MAPK BmHog1p induced by high-osmolarity stress and fungicide treatments was only regulated by ChSsk1p, indicating that ChSkn7p has roles in high-osmolarity adaptation and fungicide sensitivity that are independent from the activation of BmHog1p. The Chssk1 Chskn7 double mutants clearly showed higher sensitivity to osmolar stress and higher resistance to fungicides than the single mutants. The dose responses of the double mutants fit well with those of the group III histidine kinase-deficient strain. These results suggest that in filamentous ascomycetes, the Ssk1- and Skn7-type response regulators control high-osmolarity adaptation and fungicide sensitivity additively with differential mechanisms under the regulation of the group III histidine kinase. This study provides evidence that filamentous fungi have a unique two-component signaling system that is different from that of yeast and is responsible for high-osmolarity adaptation and fungicide sensitivity.

Adaptation, Physiological↗

PubMed1998

Phosphorylation-independent activity of the response regulators AlgB and AlgR in promoting alginate biosynthesis in mucoid Pseudomonas aeruginosa.

Overproduction of the capsular polysaccharide alginate appears to confer a selective advantage for Pseudomonas aeruginosa in the lungs of cystic fibrosis patients. The regulators AlgB and AlgR, which are both required as positive activators in alginate overproduction, have homology with the regulator class of two-component environmental responsive proteins which coordinate gene expression through signal transduction mechanisms. Signal transduction in this class of proteins generally occurs via autophosphorylation of the sensor kinase protein and phosphotransfer from the sensor to a conserved aspartate residue, which is present in the amino terminus of the response regulator. Recently, kinB was identified downstream of algB and was shown to encode the cognate histidine protein kinase that efficiently phosphorylates AlgB. However, we show here that a null mutation in kinB in a mucoid cystic fibrosis isolate, P. aeruginosa FRD1, did not block alginate production. The role of the conserved aspartate residue in the phosphorylation of AlgB was examined. The predicted phosphorylation site of AlgB (D59) was mutated to asparagine (N), and a derivative of an AlgB lacking the entire amino-terminal phosphorylation domain (AlgB delta1-145) was constructed. A hexahistidine tag was included at the amino terminus of the wild-type (H-AlgB), H-AlgB delta1-145, and mutant (H-AlgB.59N) AlgB proteins. These derivatives were purified by Ni2+ affinity chromatography and examined for in vitro phosphorylation by the purified sensor kinase protein, KinB. The results indicated that while KinB efficiently phosphorylated H-AlgB, no phosphorylation of H-AlgB delta1-145 or H-AlgB.D59N was apparent. An allelic exchange system was developed to transfer mutant algB alleles onto the chromosome of a P. aeruginosa algB mutant to examine the effect on alginate production. Despite the defect in AlgB phosphorylation, P. aeruginosa strains expressing AlgB.D59N or H-AlgB delta1-145 remained mucoid. The roles of the conserved aspartate residues in the phosphorylation of AlgR were also examined. As seen with AlgB, mutations in the predicted phosphorylation site of AlgR (AlgR.D54N and AlgR.D85N) did not affect alginate production. These results indicate that in vivo phosphorylation of AlgB and AlgR are not required for their roles in alginate production. Thus, the mechanism by which these response regulators activate alginate genes in mucoid P. aeruginosa appears not to be mediated by conventional phosphorylation-dependent signal transduction.

Alginates↗

PubMed2004

Sensing and responding to diverse extracellular signals? Analysis of the sensor kinases and response regulators of Streptomyces coelicolor A3(2).

Streptomyces coelicolor is a Gram-positive soil bacterium that undergoes a complex developmental life cycle. The genome sequence of this organism was recently completed and has revealed the presence of over 60 sigma factors and a multitude of other transcriptional regulators, with a significant number of these being putative two-component signal transduction proteins. The authors have used the criteria established by Hoch and co-workers (Fabret et al., 1999, J Bacteriol 181, 1975-1983) to identify sensor kinase and response regulator genes encoded within the S. coelicolor genome. This analysis has revealed the presence of 84 sensor kinase genes, 67 of which lie adjacent to genes encoding response regulators. This strongly suggests that these paired genes encode two-component systems. In addition there are 13 orphan response regulators encoded in the genome, several of which have already been characterized and are implicated in development and antibiotic production, and 17 unpaired and as yet uncharacterized sensor kinases. This article attempts to infer useful information from sequence analysis and reviews what is currently known about the two-component systems, unpaired sensor kinases and orphan response regulators of S. coelicolor from both published reports and the authors' own unpublished data.

Adaptation, Physiological↗

PubMed2005

Proteomic analysis reveals the wide-ranging effects of the novel, iron-responsive regulator RirA in Rhizobium leguminosarum bv. viciae.

The wide-ranging effects of RirA, a novel Fe-responsive regulator of gene expression in Rhizobium leguminosarum bv. viciae, were monitored on 2D gels. Approximately 100 proteins were expressed at higher levels in a RirA(-) mutant, compared to wild type. These included the products of the sufS(2)BCDS(1)XA operon, which probably specifies the synthesis of [FeS] clusters. Using lac fusions, this operon was confirmed to be regulated by RirA in response to Fe availability. Genes for some ABC transporters, and a protein that may be involved in making a phenazine-like molecule, were also repressed by Fe in a RirA-dependent way. Strikingly, at least 17 proteins were reduced in abundance in the RirA(-) mutant. These included three ABC transporters, a GatB-like enzyme involved in tRNA modification, and a protein that may confer bacteriocin resistance. As judged by lac reporter fusions, this apparently positive control by RirA was probably due to post-transcriptional effects, in at least some cases. Therefore, although RirA shows no sequence similarity to Fur or DtxR, it functions as a wide-ranging, Fe-responsive regulator.

Bacterial Proteins↗

PubMed2002

Mycobacterium bovis BCG response regulator essential for hypoxic dormancy.

Obligately aerobic tubercle bacilli are capable of adapting to survive hypoxia by developing into a nonreplicating or dormant form. Dormant bacilli maintain viability for extended periods. Furthermore, they are resistant to antimycobacterials, and hence, dormancy might play a role in the persistence of tuberculosis infection despite prolonged chemotherapy. Previously, we have grown dormant Mycobacterium bovis BCG in an oxygen-limited Wayne culture system and subjected the bacilli to proteome analysis. This work revealed the upregulation of the response regulator Rv3133c and three other polypeptides (alpha-crystallin and two "conserved hypothetical" proteins) upon entry into dormancy. Here, we replaced the coding sequence of the response regulator with a kanamycin resistance cassette and demonstrated that the loss-of-function mutant died after oxygen starvation-induced termination of growth. Thus, the disruption of this dormancy-induced transcription factor resulted in loss of the ability of BCG to adapt to survival of hypoxia. Two-dimensional gel electrophoresis of protein extracts from the gene-disrupted strain showed that the genetic loss of the response regulator caused loss of the induction of the other three dormancy proteins. Thus, the upregulation of these dormancy proteins requires the response regulator. Based on these two functions, dormancy survival and regulation, we named the Rv3133c gene dosR for dormancy survival regulator. Our results provide conclusive evidence that DosR is a key regulator in the oxygen starvation-induced mycobacterial dormancy response.

Anaerobiosis↗

PubMed2024

PSEUDO-RESPONSE REGULATOR 3b and transcription factor ABF3 modulate abscisic acid-dependent drought stress response in soybean.

The circadian system plays a pivotal role in facilitating the ability of crop plants to respond and adapt to fluctuations in their immediate environment effectively. Despite the increasing comprehension of PSEUDO-RESPONSE REGULATORs and their involvement in the regulation of diverse biological processes, including circadian rhythms, photoperiodic control of flowering, and responses to abiotic stress, the transcriptional networks associated with these factors in soybean (Glycine max (L.) Merr.) remain incompletely characterized. In this study, we provide empirical evidence highlighting the significance of GmPRR3b as a crucial mediator in regulating the circadian clock, drought stress response, and abscisic acid (ABA) signaling pathway in soybeans. A comprehensive analysis of DNA affinity purification sequencing and transcriptome data identified 795 putative target genes directly regulated by GmPRR3b. Among them, a total of 570 exhibited a significant correlation with the response to drought, and eight genes were involved in both the biosynthesis and signaling pathways of ABA. Notably, GmPRR3b played a pivotal role in the negative regulation of the drought response in soybeans by suppressing the expression of abscisic acid-responsive element-binding factor 3 (GmABF3). Additionally, the overexpression of GmABF3 exhibited an increased ability to tolerate drought conditions, and it also restored the hypersensitive phenotype of the GmPRR3b overexpressor. Consistently, studies on the manipulation of GmPRR3b gene expression and genome editing in plants revealed contrasting reactions to drought stress. The findings of our study collectively provide compelling evidence that emphasizes the significant contribution of the GmPRR3b-GmABF3 module in enhancing drought tolerance in soybean plants. Moreover, the transcriptional network of GmPRR3b provides valuable insights into the intricate interactions between this gene and the fundamental biological processes associated with plant adaptation to diverse environmental conditions.

Glycine max↗

PubMed1998

An Arabidopsis protein that interacts with the cytokinin-inducible response regulator, ARR4, implicated in the His-Asp phosphorylay signal transduction.

Previously, Arabidopsis thaliana was shown to possess a set of response regulators (ARR-series), which are implicated in the prokaryotic type of signal transduction mechanism, generally referred to as the His-Asp phosphorylay. Among them, ARR4 is a typical phospho-accepting response regulator, whose expression was recently demonstrated to be rapidly induced by a cytokinin-treatment of the plant. To gain insight into the presumed His-Asp phosphotransfer signaling mechanism as well as the role of ARR4 in this higher plant, in this study we adopt the widely used yeast two-hybrid system, and report the identification of an Arabidopsis protein that has an ability to interact physically with the cytokinin-inducible ARR4 response regulator.

Amino Acid Sequence↗