Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.13.3 (histidine kinase)
2,405 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

His-Asp phosphorelays are widespread signal transduction mechanisms in bacteria, fungi, and higher plants. In order to investigate a His-Asp phosphorelay network in filamentous fungi, which has been genetically characterized in part, we attempted to construct an in vitro phosphotransfer network in Aspergillus nidulans comprising all the necessary components. As a first step, we established an in vitro phosphotransfer system with a histidine-containing phosphotransmitter YpdA, a response regulator SrrA, and a bacterial histidine kinase ArcB as a phosphate donor. We demonstrated the phosphotransfer from ArcB to A. nidulans YpdA and the subsequent transfer from YpdA to SrrA. This is the first direct biochemical evidence for the presence of the phosphotransfer system in filamentous fungi. Furthermore, a retrograde phosphorylation from YpdA to FphA, a histidine kinase similar to bacterial phytochrome, was found. The overall picture of the His-Asp phosphorelays in A. nidulans is discussed based on the results of the in vitro study.
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PMID:In vitro analysis of His-Asp phosphorelays in Aspergillus nidulans: the first direct biochemical evidence for the existence of His-Asp phosphotransfer systems in filamentous fungi. 1792 4

His-Asp phosphorelays are signal transduction mechanisms widely found in both prokaryotes and eukaryotes. The phosphorelay comprises three types of signal transducers: a sensor with histidine kinase (HK), a response regulator containing a phospho-accepting receiver (RR), and a histidine-containing phosphotransmitter (HPt). In this study, we examined HK expression using a green fluorescent protein (GFP) reporter driven by HK promoters in Aspergillus nidulans. All the transformants showed fluorescence derived from GFP in a submerged culture, although some of them were very weak, indicating that all the promoters were active. As judged by the fluorescence of transformants grown on a culture plate on which sexual development was induced, promoters of fphA, hk-8-2, and hk-8-5 preferentially functioned in conidial heads, the promoter of phkA preferentially functioned in cleistothecia, and the promoters of tcsB and nikA function in both conidial heads and cleistothecia. These results indicate that at least some HKs of A. nidulans showed temporally and spatially different expression during the cell cycle.
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PMID:GFP-tagged expression analysis revealed that some histidine kinases of Aspergillus nidulans show temporally and spatially different expression during the life cycle. 1825 1

The PhoP-PhoQ two-component system is a well studied bacterial signaling system that regulates virulence and stress response. Catalytic activity of the histidine kinase sensor protein PhoQ is activated by low extracellular concentrations of divalent cations such as Mg2+, and subsequently the response regulator PhoP is activated in turn through a classic phosphotransfer pathway that is typical in such systems. The PhoQ sensor domains of enteric bacteria contain an acidic cluster of residues (EDDDDAE) that has been implicated in direct binding to divalent cations. We have determined crystal structures of the wild-type Escherichia coli PhoQ periplasmic sensor domain and of a mutant variant in which the acidic cluster was neutralized to conservative uncharged residues (QNNNNAQ). The PhoQ domain structure is similar to that of DcuS and CitA sensor domains, and this PhoQ-DcuS-CitA (PDC) sensor fold is seen to be distinct from the superficially similar PAS domain fold. Analysis of the wild-type structure reveals a dimer that allows for the formation of a salt bridge across the dimer interface between Arg-50' and Asp-179 and with nickel ions bound to aspartate residues in the acidic cluster. The physiological importance of the salt bridge to in vivo PhoQ function has been confirmed by mutagenesis. The mutant structure has an alternative, non-physiological dimeric association.
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PMID:Crystal structure of a functional dimer of the PhoQ sensor domain. 1834 79

A response regulator, NblR, of the cyanobacterium Synechococcus elongatus PCC 7942 is known to induce expression of the nblA gene, a key factor in phycobilisome degradation (bleaching) under nutrient-deprivation conditions. In this study, we observed phosphorylation-independent regulation of NblR activity. We constructed a mutant strain expressing NblR (D57A), in which a putative phospho-accepting Asp-57 was replaced with Ala residue. Under nitrogen deprivation, this strain exhibited the typical bleaching phenotype observed in wild-type cells. Moreover, in the mutant, the nblA transcript accumulated at a level similar to that of the wild type. Our results indicate that activation of NblR is independent of phosphorylation, if any, by a cognate histidine kinase. Screening of proteins interacting with NblR by yeast two-hybrid analysis revealed two candidates, MreC and NarB, suggesting a novel mechanism that activates NblR, or other functions of the response regulator.
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PMID:NblR is a novel one-component response regulator in the cyanobacterium Synechococcus elongatus PCC 7942. 1839 40

The Frz chemosensory system is a two-component signal transduction pathway that controls cell reversals and directional movements for the two motility systems in Myxococcus xanthus. To trigger cell reversals, FrzE, a hybrid CheA-CheY fusion protein, autophosphorylates the kinase domain at His-49, and phosphoryl groups are transferred to aspartate residues (Asp-52 and Asp-220) in the two receiver domains of FrzZ, a dual CheY-like protein that serves as the pathway output. The role of the receiver domain of FrzE was unknown. In this paper, we characterize the FrzE protein in vitro and show that the receiver domain of FrzE negatively regulates the autophosphorylation activity of the kinase domain of FrzE. Unexpectedly, it does not appear to play a direct role in phospho-relay as in most other histidine kinase receiver domain hybrid systems. The regulatory role of the FrzE receiver domain suggests that it may interact with or be phosphorylated by an unknown protein. We also show the dynamics of motility system-specific marker proteins in FrzE mutants as cells move forward and reverse. Our studies indicate that the two motility systems are functionally co-ordinated and that any system-specific branching of the pathway most likely occurs downstream of FrzE.
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PMID:The receiver domain of FrzE, a CheA-CheY fusion protein, regulates the CheA histidine kinase activity and downstream signalling to the A- and S-motility systems of Myxococcus xanthus. 1843 Jan 34

Anaplasma phagocytophilum, the etiologic agent of human granulocytic anaplasmosis (HGA), has genes predicted to encode three sensor kinases, one of which is annotated PleC, and three response regulators, one of which is PleD. Prior to this study, the roles of PleC and PleD in the obligatory intracellular parasitism of A. phagocytophilum and their biochemical activities were unknown. The present study illustrates the relevance of these factors by demonstrating that both pleC and pleD were expressed in an HGA patient. During A. phagocytophilum development in human promyelocytic HL-60 cells, PleC and PleD were synchronously upregulated at the exponential growth stage and downregulated prior to extracellular release. A recombinant PleC kinase domain (rPleCHKD) has histidine kinase activity; no activity was observed when the conserved site of phosphorylation was replaced with alanine. A recombinant PleD (rPleD) has autokinase activity using phosphorylated rPleCHKD as the phosphoryl donor but not with two other recombinant histidine kinases. rPleCHKD could not serve as the phosphoryl donor for a mutant rPleD (with a conserved aspartic acid, the site of phosphorylation, replaced by alanine) or two other A. phagocytophilum recombinant response regulators. rPleD had diguanylate cyclase activity to generate cyclic (c) di-GMP from GTP in vitro. UV cross-linking of A. phagocytophilum lysate with c-di-[(32)P]GMP detected an approximately 47-kDa endogenous protein, presumably c-di-GMP downstream receptor. A new hydrophobic c-di-GMP derivative, 2'-O-di(tert-butyldimethylsilyl)-c-di-GMP, inhibited A. phagocytophilum infection in HL-60 cells. Our results suggest that the two-component PleC-PleD system is a diguanylate cyclase and that a c-di-GMP-receptor complex regulates A. phagocytophilum intracellular infection.
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PMID:The Anaplasma phagocytophilum PleC histidine kinase and PleD diguanylate cyclase two-component system and role of cyclic Di-GMP in host cell infection. 1904 57

The Rcs (regulator of capsule synthesis) signalling complex comprises the membrane-associated hybrid sensor kinases RcsC and RcsD, the transcriptional regulator RcsB and the two co-inducers RcsA and RcsF. Acting as a global regulatory network, the Rcs phosphorelay controls multiple cellular pathways including capsule synthesis, cell division, motility, biofilm formation and virulence mechanisms. Signal-dependent communication of the individual Rcs domains showing histidine kinase, phosphoreceiver, phosphoryl transfer and DNA-binding activities is characteristic and essential for the modulation of signal transfer. We have analysed the structures of core elements of the Rcs network including the RcsC-PR (phosphoreceiver domain of RcsC) and the RcsD-HPt (histidine phosphotransfer domain of RcsD), and we have started to characterize the dynamics and recognition mechanisms of the proteins. RcsC-PR represents a typical CheY-like alpha/beta/alpha sandwich fold and it shows a large conformational flexibility near the active-site residue Asp(875). NMR analysis revealed that RcsC-PR is able to adopt preferred conformations upon Mg(2+) co-ordination, BeF(3)(-) activation, phosphate binding and RcsD-HPt recognition. In contrast, the alpha-helical structure of RcsD-HPt is conformationally stable and contains a recognition area in close vicinity to the active-site His(842) residue. Our studies indicate the importance of protein dynamics and conformational exchange for the differential response to the variety of signals perceived by complex regulatory networks.
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PMID:Modulation of the Rcs-mediated signal transfer by conformational flexibility. 1902 69

Adaptive signal transduction within microbial cells involves a multi-faceted regulated phosphotransfer mechanism that comprises structural rearrangements of sensor histidine kinases upon ligand-binding and phosphorylation-induced conformational changes in response regulators of versatile two-component systems (TCS), arisen early in bacterial evolution. In Escherichia coli, cross-talk between the AtoS histidine kinase and the AtoC response regulator, forming the AtoSC TCS, through His --> Asp phosphotransfer, activates AtoC directly to induce atoDAEB operon expression, thus modulating diverse fundamental cellular processes such as short-chain fatty acid catabolism, poly-(R)-3-hydroxybutyrate biosynthesis and chemotaxis. Among the inducers hitherto identified, acetoacetate is the classical activator. The AtoSC TCS functional modulation by polyamines, histamine and Ca(2+), as well as the role of AtoC as transcriptional regulator, add new promising perspectives in the physiological significance and potential pharmacological exploitation of this TCS in cell proliferation, bacteria-host interactions, chemotaxis, and adaptation.
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PMID:Signal transduction and adaptive regulation through bacterial two-component systems: the Escherichia coli AtoSC paradigm. 1919 78

Uropathogenic Escherichia coli (UPEC) can grow in environments with significantly elevated osmolarities, such as murine and human urinary tracts. OmpR is the response regulator part of a two-component OmpR-EnvZ regulatory system that responds to osmotic stresses. To determine the role of OmpR in UPEC survival, a DeltaompR mutant was created in the UPEC clinical isolate NU149. The DeltaompR mutant had a growth defect compared with the wild-type strain under osmotic stress conditions; this defect was complemented by the full-length ompR gene on a plasmid, but not with a mutant OmpR with an alanine substitution for aspartic acid at the phosphorylation site at position 55. Furthermore, the DeltaompR mutant displayed up to 2-log reduction in bacterial cell numbers in murine bladders and kidneys compared with wild-type bacteria after 5 days of infection. The ability of the bacteria to survive was restored to wild-type levels when the DeltaompR mutant strain was complemented with wild-type ompR, but not when the alanine-substituted ompR gene was used. This study has fulfilled molecular Koch's postulates by showing the pivotal role OmpR plays in UPEC survival within the murine urinary tract.
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PMID:Survival of uropathogenic Escherichia coli in the murine urinary tract is dependent on OmpR. 1938

Here we introduce a quantitative structure-driven computational domain-fusion method, which we used to predict the structures of proteins believed to be involved in regulation of the subtilin pathway in Bacillus subtilis, and used to predict a protein-protein complex formed by interaction between the proteins. Homology modeling of SpaK and SpaR yielded preliminary structural models based on a best template for SpaK comprising a dimer of a histidine kinase, and for SpaR a response regulator protein. Our LGA code was used to identify multi-domain proteins with structure homology to both modeled structures, yielding a set of domain-fusion templates then used to model a hypothetical SpaK/SpaR complex. The models were used to identify putative functional residues and residues at the protein-protein interface, and bioinformatics was used to compare functionally and structurally relevant residues in corresponding positions among proteins with structural homology to the templates. Models of the complex were evaluated in light of known properties of the functional residues within two-component systems involving His-Asp phosphorelays. Based on this analysis, a phosphotransferase complexed with a beryllofluoride was selected as the optimal template for modeling a SpaK/SpaR complex conformation. In vitro phosphorylation studies performed using wild type and site-directed SpaK mutant proteins validated the predictions derived from application of the structure-driven domain-fusion method: SpaK was phosphorylated in the presence of (32)P-ATP and the phosphate moiety was subsequently transferred to SpaR, supporting the hypothesis that SpaK and SpaR function as sensor and response regulator, respectively, in a two-component signal transduction system, and furthermore suggesting that the structure-driven domain-fusion approach correctly predicted a physical interaction between SpaK and SpaR. Our domain-fusion algorithm leverages quantitative structure information and provides a tool for generation of hypotheses regarding protein function, which can then be tested using empirical methods.
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PMID:SpaK/SpaR two-component system characterized by a structure-driven domain-fusion method and in vitro phosphorylation studies. 1950 43


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