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PubMed2004

Survey of the number of two-component response regulator genes in the complete and annotated genome sequences of prokaryotes.

The numbers of potential response regulator genes were determined from the complete and annotated genome sequences of Archaea and Bacteria. The numbers of each class of response regulators are shown for each organism, determined principally from BLASTP searches, but with reference to the gene category lists where available. The survey shows that for Bacteria there is a link between the total number of potential response regulator genes and both the genome complexity (number of potential protein-coding genes) and the organism's lifestyle/habitat. Increasingly complex lifestyles and genome complexities are matched by an increase in the average number of potential response regulator genes per genome, indicating that a higher degree of complexity requires a higher level of control of gene expression and cellular activity. Detailed results of this study are available online at and.

Data Collection↗
PubMed2006

Cyanobacterial response regulator PatA contains a conserved N-terminal domain (PATAN) with an alpha-helical insertion.

The cyanobacterium Anabaena (Nostoc) PCC 7120 responds to starvation for nitrogen compounds by differentiating approximately every 10th cell in the filament into nitrogen-fixing cells called heterocysts. Heterocyst formation is subject to complex regulation, which involves an unusual response regulator PatA that contains a CheY-like phosphoacceptor (receiver, REC) domain at its C-terminus. PatA-like response regulators are widespread in cyanobacteria; one of them regulates phototaxis in Synechocystis PCC 6803. Sequence analysis of PatA revealed, in addition to the REC domain, a previously undetected, conserved domain, which we named PATAN (after PatA N-terminus), and a potential helix-turn-helix (HTH) domain. PATAN domains are encoded in a variety of environmental bacteria and archaea, often in several copies per genome, and are typically associated with REC, Roadblock and other signal transduction domains, or with DNA-binding HTH domains. Many PATAN domains contain insertions of a small additional domain, termed alpha-clip, which is predicted to form a four-helix bundle. PATAN domains appear to participate in protein-protein interactions that regulate gliding motility and processes of cell development and differentiation in cyanobacteria and some proteobacteria, such as Myxococcus xanthus and Geobacter sulfurreducens.

Amino Acid Sequence↗
PubMed1998

Phosphorylation of the Spo0B response regulator phosphotransferase of the phosphorelay initiating development in Bacillus subtilis.

The initiation of sporulation in Bacillus subtilis is regulated by the phosphorelay, a complex signal transduction system consisting of kinases and response regulators. The key component of a phosphorelay is the phosphotransferase, which recognizes two response regulators and transfers a phosphoryl group between them. In this reaction, the phosphoryl of one response regulator is transferred to a histidine on the phosphotransferase before phosphorylating an aspartate of the second response regulator. The phosphorylated histidine on the Spo0B phosphotransferase was found to be His30. Site-directed mutation of His30 to alanine destroyed its phosphotransferase activity in vitro and strains constructed with this mutation were unable to sporulate. None of the other 10 histidines of Spo0B was implicated in the phosphotransferase reaction. A structurally vulnerable site, histidine 23, was also identified through the mutational study. The His30 of Spo0B resides in a domain with little sequence homology to functionally equivalent domains in the phosphorelays of other bacterial and yeast systems, suggesting that the two types of phosphotransfer domains evolved convergently.

Amino Acid Sequence↗
PubMed2003

Molecular characterization of the essential response regulator protein YycF in Bacillus subtilis.

The response regulator YycF is essential for cell growth in gram-positive bacteria including Bacillus subtilis, Staphylococcus aureus and Streptococcus pneumoniae. To study the function of YycF in the essential process, we characterized a YycF (H215P) mutation that caused temperature-sensitive growth in B. subtilis. The response regulators YycF and YycF (H215P) were analyzed using circular dichroism spectroscopy, whose T(m) values were 56.0 and 45.9 degrees C, respectively, suggesting that YycF (H215P) significantly affects the protein structure with an increase in temperature. Furthermore, using the gel mobility shift assay and DNase I footprinting, we investigated the effect of YycF (H215P) on binding to the YycF box of ftsAZ operon of B. subtilis. The replacement of the histidine 215 with proline resulted in a decrease of the DNA-binding ability of YycF in vitro. In vivo, using Escherichia coli two-hybrid and homodimerization assays, we clarified that His 215 of YycF plays a crucial role in the homodimerization of the protein. Thus the essential genes involved in growth of B. subtilis appear to be regulated by the homodimer of YycF. These results suggest that the YycF dimerization is an excellent target for the discovery of novel antibiotics.

Amino Acid Sequence↗
PubMed2002

Interaction surface of the Spo0A response regulator with the Spo0E phosphatase.

Spo0A~P is the essential response regulator and transcription factor for sporulation initiation in Bacillus subtilis. The phosphorylation level of Spo0A in the cell is determined by the sensor kinase activity of the phosphorelay, donating phosphoryl groups, and the antagonistic effects of dephosphorylation mediated by the Rap and Spo0E families of phosphatases. In this study, spo0A mutations were generated that encoded proteins less sensitive to the activity of Spo0E than the wild-type protein. The Spo0A substitutions N12K, P60S, L62P and F88L are surface exposed and localize to the same face of the molecule as the active site and in its close proximity on the beta1-alpha1, beta3-alpha3 and beta4-alpha4 loops. The corresponding surface in the Spo0F response regulator was shown previously to be involved in the interaction with the RapB phosphatase, as well as the KinA histidine kinase and the Spo0B phosphotransferase. Thus, residues occupying the same position (N12:Q12, F88:Y84) and the same loops in Spo0A or Spo0F are involved in the interaction with the structurally unrelated Spo0E and RapB phosphatases, respectively, in addition to kinases and phosphotransferase. The specificity in phosphatase target recognition must be the result of side-chain variability within the response regulators and the interactions they promote. The residues involved in Spo0E interaction are identical in all Spo0A orthologues from spore-forming Bacilli encoding Spo0E phosphatases.

Amino Acid Sequence↗
PubMed1999

Compilation and characterization of Arabidopsis thaliana response regulators implicated in His-Asp phosphorelay signal transduction.

His-Asp phosphorelays are evolutionary-conserved powerful biological tactics for intracellular signal transduction. Such a phosphorelay is generally made up of "sensor histidine (His)-kinases", "response regulators", and "histidine-containing (HPt) phosphotransmitters". In the higher plant, Arabidopsis thaliana, results from recent intensive studies suggested that His-Asp phosphorelays may be widely used for propagating environmental stimuli, such as phytohormones (e.g., ethylene and cytokinin). In this study, we first inspected extensively the occurrence of Arabidopsis response regulators in order to compile and characterize them. The results showed that this higher plant has, at least, 14 members of the family of response regulators that can be classified into two distinct subtypes (type-A and type-B), as judged from their structural designs, biochemical properties, and expression profiles. Comparative studies were conducted for each representative (ARR3 and ARR4 for type-A, and ARR10 for type-B). It was suggested that expression of the type-A response regulator is cytokinin-inducible, while that of the type-B response regulator appears to be not. Results from yeast two-hybrid analyses suggested that the type-B response regulator may have an ability to stably interact with a set of HPt phosphotransmitters (AHPs). These and other results will be discussed with special reference to the His-Asp phosphorelay signaling network in Arabidopsis thaliana.

Amino Acid Sequence↗
PubMed2000

A role for Asp75 in domain interactions in the Bacillus subtilis response regulator Spo0A.

Spo0A is a two-domain response regulator required for sporulation initiation in Bacillus subtilis. Studies on response regulators have focused on the activity of each domain, but very little is known about the mechanism by which the regulatory domain inhibits the activator domain. In this study, we created a single amino acid substitution in the regulatory domain, D75S, which resulted in a dramatic decrease in sporulation in vivo. In vitro studies with the purified Spo0AD75S protein demonstrated that phosphorylation and DNA binding were comparable with wild type Spo0A. However, the mutant was unable to stimulate transcription by final sigma(A)-RNA polymerase from the Spo0A-dependent spoIIG operon promoter. We suggest that the amino acid Asp(75) and/or the region within which it resides, the alpha3-beta4 loop, are involved in the inhibitory interaction between the regulatory and activator domains of Spo0A.

Asparagine↗
PubMed2002

Growth phase-dependent regulation of target gene promoters for binding of the essential orphan response regulator HP1043 of Helicobacter pylori.

Helicobacter pylori encodes three two-component systems and two orphan response regulators (RRs) that are predicted to be involved in transcriptional regulation. The HP1043 gene encodes an essential OmpR-like RR, 1043RR, for which no histidine kinase has been identified. Gel filtration and cross-linking experiments on the purified 1043RR protein reveals that this protein is a dimer and in vivo dimerization assays localize the dimerization to the N-terminal regulatory domain. DNA-binding studies have revealed two targets for specific binding of the 1043RR protein and moreover, phosphorylation of the protein was not needed for the activation of binding. Footprinting analysis demonstrated that the 1043RR protein binds to its own promoter, P(1043), overlapping the -35 promoter element from positions -17 to -45, suggesting that this protein is autoregulatory. In addition, it binds at a similar location, spanning nucleotides from positions -22 to -51 at the promoter of the methyl-accepting chemotaxis tlpB gene, P(tlpB). A possible inverted repeat was identified in the binding sites of both promoters. In an attempt to overexpress 1043RR in H. pylori, the 10-fold induction in transcription of a second copy of HP1043 with use of an inducible promoter failed to increase cellular levels of the RR protein, suggesting that 1043RR is tightly regulated at a posttranscriptional level. The P(1043) and P(tlpB) promoters were demonstrated to be coordinately regulated in response to growth phase in H. pylori. The essential role of HP1043 in encoding a cell cycle regulator is discussed.

Bacterial Proteins↗
PubMed2005

Pseudo-Response Regulators (PRRs) or True Oscillator Components (TOCs).

In Arabidopsis thaliana, AUTHENTIC RESPONSE REGULATORS (ARRs) act as downstream components of the His-to-Asp phosphorelay (two-component) signaling pathway that is propagated primarily by the cytokinin receptor kinases, AUTHENTIC HIS-KINASES (AHK2, AHK3 and AHK4/CRE1). Thus, this bacterial type of signaling system is essential for responses to a class of hormones in plants. Interestingly, this higher plant has also evolved its own atypical (or unique) variants of two-component signal transducers, PSEUDO-RESPONSE REGULATORS (PRRs). Several lines of recent results suggest that the functions of PRRs are closely relevant to the plant clock (oscillator) that is central to circadian rhythms, the underlying mechanisms of which have long been the subject of debate. Through an overview of recent results, the main issue addressed here is whether or not the pseudo-response regulators (PRRs) are true oscillator components (TOCs).

Arabidopsis↗
PubMed2005

Transcriptional regulation of the flavohemoglobin gene for aerobic nitric oxide detoxification by the second nitric oxide-responsive regulator of Pseudomonas aeruginosa.

The regulatory gene for a sigma54-dependent-type transcriptional regulator, fhpR, is located upstream of the fhp gene for flavohemoglobin in Pseudomonas aeruginosa. Transcription of fhp was induced by nitrate, nitrite, nitric oxide (NO), and NO-generating reagents. Analysis of the fhp promoter activity in mutant strains deficient in the denitrification enzymes indicated that the promoter was regulated by NO or related reactive nitrogen species. The NO-responsive regulation was operative in a mutant strain deficient in DNR (dissimilatory nitrate respiration regulator), which is the NO-responsive regulator required for expression of the denitrification genes. A binding motif for sigma54 was found in the promoter region of fhp, but an FNR (fumarate nitrate reductase regulator) box was not. The fhp promoter was inactive in the fhpR or rpoN mutant strain, suggesting that the NO-sensing regulation of the fhp promoter was mediated by FhpR. The DNR-dependent denitrification promoters (nirS, norC, and nosR) were active in the fhpR or rpoN mutants. These results indicated that P. aeruginosa has at least two independent NO-responsive regulatory systems. The fhp or fhpR mutant strains showed sensitivity to NO-generating reagents under aerobic conditions but not under anaerobic conditions. These mutants also showed significantly low aerobic NO consumption activity, indicating that the physiological role of flavohemoglobin in P. aeruginosa is detoxification of NO under aerobic conditions.

Aerobiosis↗
PubMed2005

An active-like structure in the unphosphorylated StyR response regulator suggests a phosphorylation- dependent allosteric activation mechanism.

StyR belongs to the FixJ subfamily of signal transduction response regulators; it controls transcription of the styABCD operon coding for styrene catabolism in Pseudomonas fluorescens ST. The crystal structure of unphosphorylated StyR is reported at 2.2 A resolution. StyR is composed of an N-terminal regulatory domain (StyR-N) and a C-terminal DNA binding domain (StyR-C). The two domains are separated by an elongated linker alpha helix (34 residues), a new feature in known response regulator structures. StyR-C is structured similarly to the DNA binding domain of the response regulator NarL. StyR-N shows structural reorganization of the phosphate receiving region involved in activation/homodimerization: specific residues adopt an "active-like" conformation, and the alpha4 helix, involved in dimerization of the homologous FixJ response regulator, is trimmed to just one helical turn. Overall, structural considerations suggest that phosphorylation may act as an allosteric switch, shifting a preexisting StyR equilibrium toward the active, dimeric, DNA binding form.

Allosteric Regulation↗
PubMed2005

The Campylobacter jejuni response regulator, CbrR, modulates sodium deoxycholate resistance and chicken colonization.

Two-component regulatory systems play a major role in the physiological response of bacteria to environmental stimuli. Such systems are composed of a sensor histidine kinase and a response regulator whose ultimate function is to affect the expression of target genes. Response regulator mutants of Campylobacter jejuni strain F38011 were screened for sensitivity to sodium deoxycholate. A mutation in Cj0643, which encodes a response regulator with no obvious cognate histidine kinase, resulted in an absence of growth on plates containing a subinhibitory concentration of sodium deoxcholate (1%, wt/vol). In broth cultures containing 0.05% (wt/vol) sodium deoxycholate, growth of the mutant was significantly inhibited compared to growth of the C. jejuni F38011 wild-type strain. Complementation of the C. jejuni cbrR mutant in trans restored growth in both broth and plate cultures supplemented with sodium deoxycholate. Based on the phenotype displayed by its mutation, we designated the gene corresponding to Cj0643 as cbrR (Campylobacter bile resistance regulator). While the MICs of a variety of bile salts and other detergents for the C. jejuni cbrR mutant were lower, no difference was noted in its sensitivity to antibiotics or osmolarity. Finally, chicken colonization studies demonstrated that the C. jejuni cbrR mutant had a reduced ability to colonize compared to the wild-type strain. These data support previous findings that bile resistance contributes to colonization of chickens and establish that the response regulator, CbrR, modulates resistance to bile salts in C. jejuni.

Amino Acid Sequence↗
PubMed1998

Identification of communication networks in Spo0F: a model for phosphorylation-induced conformational change and implications for activation of multiple domain bacterial response regulators.

Fundamental to understanding the mechanism by which phosphorylation activates bacterial signal transduction response regulator proteins is the identification of regions and residues that are responsible for the phosphorylation-induced conformational change. Here we review results from structural and protein dynamics investigations, and combine them with mutagenesis studies on the response regulator protein SpoOF to suggest a model in which a network of buried and surface residues link surface regions required for protein:protein interactions to the site of phosphorylation. The network described for SpoOF may provide pathways through which information is transmitted from the site of phosphorylation, propagating a conformational change many angstroms away. The general applicability of the communication network model for all bacterial response regulator proteins is discussed.

Bacterial Proteins↗
PubMed2000

Defective hyphal development and avirulence caused by a deletion of the SSK1 response regulator gene in Candida albicans.

In a previous study, we reported the isolation and characterization of the two-component response regulator SSK1 gene of Candida albicans. This gene is a structural but not a functional homolog of the SSK1 and mcs4(+) genes of Saccharomyces cerevisiae and Schizosaccharomyces pombe, respectively. In the present study, we have constructed and phenotypically characterized Deltassk1 mutants of C. albicans. The results confirmed our previous observation that CaSSK1, unlike SSK1 or mcs4(+), does not regulate cellular responses to either osmotic or oxidative stress. Instead, Deltassk1 null strains showed severely reduced hyphal formation on serum agar and were totally defective in hyphal development on other solid media, such as medium 199 (pH 7.5) and Spider medium. In contrast, under conditions of low nitrogen availability on solid media, Deltassk1 null strains dramatically hyperinvaded the agar. However, while forming germ tubes and hyphae in liquid media similar to those of the wild type, Deltassk1 null strains flocculated in a manner similar to that of Deltachk1 two-component histidine kinase mutants, which we have previously described. Finally, virulence studies indicated that SSK1 is essential for the pathogenesis of C. albicans, suggesting that the Ssk1p response regulator could be a good target for antifungal therapy.

Animals↗
PubMed2006

Structural classification of bacterial response regulators: diversity of output domains and domain combinations.

CheY-like phosphoacceptor (or receiver [REC]) domain is a common module in a variety of response regulators of the bacterial signal transduction systems. In this work, 4,610 response regulators, encoded in complete genomes of 200 bacterial and archaeal species, were identified and classified by their domain architectures. Previously uncharacterized output domains were analyzed and, in some cases, assigned to known domain families. Transcriptional regulators of the OmpR, NarL, and NtrC families were found to comprise almost 60% of all response regulators; transcriptional regulators with other DNA-binding domains (LytTR, AraC, Spo0A, Fis, YcbB, RpoE, and MerR) account for an additional 6%. The remaining one-third is represented by the stand-alone REC domain (approximately 14%) and its combinations with a variety of enzymatic (GGDEF, EAL, HD-GYP, CheB, CheC, PP2C, and HisK), RNA-binding (ANTAR and CsrA), protein- or ligand-binding (PAS, GAF, TPR, CAP_ED, and HPt) domains, or newly described domains of unknown function. The diversity of domain architectures and the abundance of alternative domain combinations suggest that fusions between the REC domain and various output domains is a widespread evolutionary mechanism that allows bacterial cells to regulate transcription, enzyme activity, and/or protein-protein interactions in response to environmental challenges. The complete list of response regulators encoded in each of the 200 analyzed genomes is available online at http://www.ncbi.nlm.nih.gov/Complete_Genomes/RRcensus.html.

Amino Acid Sequence↗
PubMed2004

Characterization of DegU, a response regulator in Listeria monocytogenes, involved in regulation of motility and contributes to virulence.

The degU (lmo2515) gene encodes a putative response regulator in the food-borne pathogen Listeria monocytogenes. It has 63% amino acid identity to the DegU response regulator of Bacillus subtilis. We have characterized the degU gene product in L. monocytogenes EGD by generation of a deletion mutant. The DeltadegU mutant was found to be non-motile in motility plate assay and no flagellin was detected. The mutant was attenuated in challenge of mice. Northern blot analysis suggested that the degU gene product is a transcriptional activator of the flagellin gene, flaA, at 25 degrees C. However, the degU gene product had no influence on the transcription of prfA encoding the major virulence regulator, PrfA. The results indicate that the putative DegU response regulator is a pleiotropic regulator involved in expression of both motility at low temperature and in vivo virulence in mice.

Adaptation, Physiological↗
PubMed2004

Type-A Arabidopsis response regulators are partially redundant negative regulators of cytokinin signaling.

Type-A Arabidopsis (Arabidopsis thaliana) response regulators (ARRs) are a family of 10 genes that are rapidly induced by cytokinin and are highly similar to bacterial two-component response regulators. We have isolated T-DNA insertions in six of the type-A ARRs and constructed multiple insertional mutants, including the arr3,4,5,6,8,9 hextuple mutant. Single arr mutants were indistinguishable from the wild type in various cytokinin assays; double and higher order arr mutants showed progressively increasing sensitivity to cytokinin, indicating functional overlap among type-A ARRs and that these genes act as negative regulators of cytokinin responses. The induction of cytokinin primary response genes was amplified in arr mutants, indicating that the primary response to cytokinin is affected. Spatial patterns of ARR gene expression were consistent with partially redundant function of these genes in cytokinin signaling. The arr mutants show altered red light sensitivity, suggesting a general involvement of type-A ARRs in light signal transduction. Further, morphological phenotypes of some arr mutants suggest complex regulatory interactions and gene-specific functions among family members.

Arabidopsis↗
PubMed2000

Novel role for an HPt domain in stabilizing the phosphorylated state of a response regulator domain.

Two-component regulatory systems that utilize a multistep phosphorelay mechanism often involve a histidine-containing phosphotransfer (HPt) domain. These HPt domains serve an essential role as histidine-phosphorylated protein intermediates during phosphoryl transfer from one response regulator domain to another. In Saccharomyces cerevisiae, the YPD1 protein facilitates phosphoryl transfer from a hybrid sensor kinase, SLN1, to two distinct response regulator proteins, SSK1 and SKN7. Because the phosphorylation state largely determines the functional state of response regulator proteins, we have carried out a comparative study of the phosphorylated lifetimes of the three response regulator domains associated with SLN1, SSK1, and SKN7 (R1, R2, and R3, respectively). The isolated regulatory domains exhibited phosphorylated lifetimes within the range previously observed for other response regulator domains (i.e., several minutes to several hours). However, in the presence of YPD1, we found that the half-life of phosphorylated SSK1-R2 was dramatically extended (almost 200-fold longer than in the absence of YPD1). This stabilization effect was specific for SSK1-R2 and was not observed for SLN1-R1 or SKN7-R3. Our findings suggest a mechanism by which SSK1 is maintained in its phosphorylated state under normal physiological conditions and demonstrate an unprecedented regulatory role for an HPt domain in a phosphorelay signaling system.

DNA-Binding Proteins↗