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)

Using a yeast two-hybrid assay system, it was demonstrated that the four-helix bundle of the Rhodobacter sphaeroides PrrB histidine kinase both serves as the interaction site for the regulatory domain of its cognate response regulator PrrA and is the primary determinant of the interaction specificity. The alpha-helix 1 and its flanking turn region within the dimerization domain (DD) of the PrrB histidine kinase appear to play an important role in conferring the recognition specificity for the PrrA response regulator on the DD. The catalytic ATP-binding domain of the histidine kinase, which functions as the catalytic unit for the phosphotransfer reaction from ATP to the conserved histidine residue in the DD, also appears to contribute to the enhancement of the recognition specificity conferred by the DD. It was also revealed that replacement of Asp-63 and Lys-113 of the PrrA response regulator by alanine abolished protein-protein interactions between PrrA and its cognate histidine kinase PrrB, whereas mutations of Asp-19, Asp-20 and Thr-87 to alanine did not affect protein-protein interactions, indicating that among the active site residues of PrrA, Asp-63 and Lys-113 are important not only in the function of PrrA but also for protein-protein interactions between PrrA and PrrB.
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PMID:Interacting specificity of a histidine kinase and its cognate response regulator: the PrrBA system of Rhodobacter sphaeroides. 1684 10

Phytochromes are light-sensing macromolecules that are part of a two component phosphorelay system controlling gene expression. Photoconversion between the Pr and Pfr forms facilitates autophosphorylation of a histidine in the dimerization domain (DHp). We report the low-resolution structure of a bacteriophytochrome (Bph) in the catalytic (CA) Pr form in solution determined by small-angle X-ray scattering (SAXS). Ab initio modeling reveals, for the first time, the domain organization in a typical bacteriophytochrome, comprising an chromophore binding and phytochrome (PHY) N terminal domain followed by a C terminal histidine kinase domain. Homologous high-resolution structures of the light-sensing chromophore binding domain (CBD) and the cytoplasmic part of a histidine kinase sensor allows us to model 75% of the structure with the remainder comprising the phytochrome domain which has no 3D representative in the structural database. The SAXS data reveal a dimeric Y shaped macromolecule and the relative positions of the chromophores (biliverdin), autophosphorylating histidine residues and the ATP molecules in the kinase domain. SAXS data were collected from a sample in the autophosphorylating Pr form and reveal alternate conformational states for the kinase domain that can be modeled in an open (no-catalytic) and closed (catalytic) state. This model suggests how light-induced signal transduction can stimulate autophosphorylation followed by phosphotransfer to a response regulator (RR) in the two-component system.
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PMID:Small-angle X-ray scattering reveals the solution structure of a bacteriophytochrome in the catalytically active Pr state. 1702 28

Nitrate transport activity of the LtnT permease of the cyanobacterium Synechococcus elongatus is activated when LtnA, a response regulator without an effector domain, is phosphorylated by LtnB, a hybrid histidine kinase. We identified a protein (LtnC) that is required for activation of LtnT. LtnC consists of an N-terminal histidine-containing phosphoacceptor (HisKA) domain, a receiver domain, and a unique C-terminal domain found in some cyanobacterial proteins. Because LtnC lacks an ATP-binding kinase domain of a histidine kinase, it is incapable of autophosphorylation, but LtnC is phosphorylated by LtnA. The histidine residue in the HisKA domain but not the aspartate residue in the receiver domain is essential for phosphorylation of LtnC and activation of LtnT. LtnC phosphorylation leads to oligomerization of the protein. Fusion of the C-terminal domain of LtnC to glutathione S-transferase, which forms oligomers, also activates LtnT, suggesting that oligomerization of the LtnC C-terminal domain causes LtnT activation. These results indicate that the C-terminal domain of LtnC acts as an effector domain that directs the output of the signal from the phosphorelay system. The two-step (His-Asp-His) phosphorelay system, composed of the LtnB, LtnA, and LtnC proteins, is distinct from the known phosphorelay systems, namely, the typical two-component system (His-Asp) and the multistep phosphorelay system (His-Asp-His-Asp), because the HisKA domain of LtnC is the terminal phosphoacceptor that determines the signal output. LtnC is a new class of signal transducer in His-Asp phosphorelay systems that contains a HisKA domain and an effector domain.
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PMID:A new class of signal transducer in His-Asp phosphorelay systems. 1704 Sep 12

Cytokinins are a class of plant hormones that regulate the cell cycle and diverse developmental and physiological processes. Several compounds have been identified that antagonize the effects of cytokinins. Based on structural similarities and competitive inhibition, it has been assumed that these anticytokinins act through a common cellular target, namely the cytokinin receptor. Here, we examined directly the possibility that various representative classical anticytokinins inhibit the Arabidopsis cytokinin receptors CRE1/AHK4 (cytokinin response 1/Arabidopsis histidine kinase 4) and AHK3 (Arabidopsis histidine kinase 3). We show that pyrrolo[2,3-d]pyrimidine and pyrazolo[4,3-d]pyrimidine anticytokinins do not act as competitors of cytokinins at the receptor level. Flow cytometry and microscopic analyses revealed that anticytokinins inhibit the cell cycle and cause disorganization of the microtubular cytoskeleton and apoptosis. This is consistent with the hypothesis that they inhibit regulatory cyclin-dependent kinase (CDK) enzymes. Biochemical studies demonstrated inhibition by selected anti-cytokinins of both Arabidopsis and human CDKs. X-ray determination of the crystal structure of a human CDK2-anticytokinin complex demonstrated that the antagonist occupies the ATP-binding site of CDK2. Finally, treatment of human cancer cell lines with anticytokinins demonstrated their ability to kill human cells with similar effectiveness as known CDK inhibitors.
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PMID:Classical anticytokinins do not interact with cytokinin receptors but inhibit cyclin-dependent kinases. 1733 23

Three different families of blue-light receptors have been characterized from higher plants: three cryptochromes, two phototropins, and the three members of the ZTL/ADO family. Phototropins and the ZTL/ADO proteins have chromophore modules, designated LOV domains, that bind flavin mononucleotide and undergo formation of a C(4a) flavin-cysteinyl adduct. All contain the highly conserved amino acid motif GXNCRFLQ. Over 90 prokaryote proteins also contain LOV domains with this motif upstream from one of several different functional groups. All of these that have been investigated to date act as photoreceptors in vitro and form the adduct upon irradiation. Four members of the class LOV-histidine kinase, one from a plant pathogen (Pseudomonas syringae), one from an animal pathogen Brucella melitensis), and two from a marine bacterium (Erythrobacter litoralis) respectively, mediate light-activated histidine phosphorylation. Decay of the adduct in darkness after a blue light pulse coincides with loss of the capacity for phosphorylation upon addition of ATP. At present, the biological role(s) of these light-sensitive proteins is under investigation.
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PMID:The LOV domain: a chromophore module servicing multiple photoreceptors. 1738 Apr 29

EnvZ is an osmosensing histidine kinase located in the inner membrane, and one of the most extensively studied Escherichia coli histidine kinases. Because of its structural complexity, functional and structural studies have been quite challenging. It is a multidomain transmembrane protein consisting of 450 amino acid residues. In addition, it must form a dimer to function as a histidine kinase like all the other histidine kinases. EnvZ consists of the 115-residue periplasmic domain, two transmembrane domains (TM1 and TM2), and the cytoplasmic domain consisting of the 43-residue linker (HAMP) domain and the 228-residue kinase domain. It has been shown that the kinase domain of EnvZ, responsible for its enzymatic activities, contains all of the conserved regions of histidine kinases such as H, F, N, G1, G2, and G3 boxes. Therefore, the 271-residue cytoplasmic domain of EnvZ (termed EnvZc) has been used as a model system to establish fundamental characteristics of histidine kinases. The DNA fragment encoding EnvZc was cloned in pET vector and EnvZc was expressed and purified. It is highly soluble and retains all the enzymatic activities of EnvZ. We demonstrated that it consists of two functional domains, domain A and domain B. NMR spectroscopic studies of these two domains revealed, for the first time, the structure of a histidine kinase. Domain A is responsible for dimerization of EnvZc forming a four-helical bundle containing two alpha-helical hairpin structures, while domain B is a monomer and has an ATP-binding pocket formed by regions conserved among the histidine kinases. In this chapter, we describe functional and structural studies of EnvZc, which can be applied to characterize other histidine kinases.
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PMID:Functional and structural characterization of EnvZ, an osmosensing histidine kinase of E. coli. 1760 32

The EnvZ/OmpR two-component regulatory system is best known for regulating the porin genes ompF and ompC in response to changes in the osmolarity of the growth medium. In response to an unknown signal, EnvZ is autophosphorylated by ATP on a histidine residue. The phosphoryl group is subsequently transferred to a conserved aspartate residue on OmpR. Phosphorylation of OmpR increases its affinity for the regulatory regions of the porin genes, altering their expression. Phosphorylation also alters the interaction with EnvZ and OmpR. In order to study the interactions of EnvZ and OmpR, we employed a full-length EnvZ construct fused to the green fluorescent protein (GFP) that was overexpressed and targeted to the inner membrane. Spheroplasts were prepared and lysed in microtiter plates containing purified, fluorescent-labeled OmpR protein. Fluorescence resonance energy transfer (FRET) from the GFP donor to fluorescein- or rhodamine-conjugated OmpR acceptor occurred, indicating that the two proteins interact. We then used FRET to further characterize the effect of phosphorylation on the interaction parameters. Results indicate that the full-length EnvZ behaves similarly to the isolated cytoplasmic domain EnvZc alone. Furthermore, the phospho-OmpR protein has a reduced affinity for the EnvZ kinase. This chapter describes general considerations regarding such experiments and provides detailed protocols for quantitatively measuring them.
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PMID:Application of fluorescence resonance energy transfer to examine EnvZ/OmpR interactions. 1762 48

The open reading frame PSPTO2896 from the plant pathogen Pseudomonas syringae pv. tomato encodes a protein of 534 amino acids showing all salient features of a blue light-driven two-component system. The N-terminal LOV (light, oxygen, voltage) domain, potentially binding a flavin chromophore, is followed by a histidine kinase (HK) motif and a response regulator (RR). The full-length protein (PST-LOV) and, separately, the RR and the LOV+HK part (PST-LOV(DeltaRR)) were heterologously expressed and functionally characterized. The two LOV proteins showed typical LOV-like spectra and photochemical reactions, with the blue light-driven, reversible formation of a covalent flavin-cysteine bond. The fluorescence changes in the lit state of full-length PST-LOV, but not in PST-LOV(DeltaRR), indicating a direct interaction between the LOV core and the RR module. Experiments performed with radioactive ATP uncover the light-driven kinase activity. For both PST-LOV and PST-LOV(DeltaRR), much more radioactivity is incorporated when the protein is in the lit state. Furthermore, addition of the RR domain to the fully phosphorylated PST-LOV(DeltaRR) leads to a very fast transfer of radioactivity, indicating a highly efficient HK activity and a tight interaction between PST-LOV(DeltaRR) and RR, possibly facilitated by the LOV core itself.
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PMID:A blue light inducible two-component signal transduction system in the plant pathogen Pseudomonas syringae pv. tomato. 1790 42

Hexokinase is the first enzyme in the glycolytic pathway and utilizes ATP to convert glucose to glucose-6-phosphate (G6P). We previously identified three variant transcripts of Hk1 that are expressed specifically in spermatogenic cells, have different 5' untranslated regions, and encode a protein (HK1S, spermatogenic cell-specific type 1 hexokinase) in which the porin-binding domain (PBD) of HK1 is replaced by a novel N-terminal spermatogenic cell-specific region (SSR). However, the level of expression of the individual variant transcripts or of the other members of the hexokinase gene family (Hk2, Hk3, and Gck) in spermatogenic cells remains uncertain. We show that Hk1, Hk2, and Hk3 transcripts levels are quite low in spermatocytes and spermatids and Gck transcripts are relatively abundant in spermatids, but that glucokinase (GCK) is not detected in spermatozoa. Using real time RT-PCR (qPCR) with primers specific for each of the three variant forms and RNA from whole testis and isolated germ cells, we found that transcripts for Hk1_v2 and Hk1_v3, but not for Hk1_v1, are relatively high in spermatids. Similar results were seen using spermatogenic cells isolated by laser-capture microdissection (LCM). Immunoblotting studies found that HK1S is abundant in sperm, and immunostaining confirmed that HK1S is located mainly in the principal piece of the sperm flagellum, where other spermatogenic cell-specific glycolytic enzymes have been found. These results strongly suggest that HK1, HK2, HK3, and GCK are unlikely to have a role in glycolysis in sperm and that HK1S encoded by Hk1_v2 and Hk1_v3 serves this role.
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PMID:Spermatogenic cell-specific type 1 hexokinase is the predominant hexokinase in sperm. 1792

Cyanobacteria respond to environmental stress conditions by adjusting its photosynthesis machinery. When subjected to nutrient and high light stress, Synechococcus sp. PCC 7942 and other non-diazotrophic cyanobacteria degrade their phycobilisome, the light-harvesting complexes for photosynthesis. Phycobilisome degradation requires convergence of multiple signals onto the nblA gene. Despite considerable efforts to identify regulatory proteins involved in acclimation responses, the signal transduction mechanisms involved remain largely unknown. However, we show here that SipA, a protein that binds to the ATP-binding domain of the histidine kinase NblS, counteracts the function of the response regulator NblR in acclimation to stress, and is also involved in downregulation of the nblA gene. The integrity of the HLR1 element overlapping P(nblA-1) and P(nblA-2) promoters is required for downregulation of the nblA gene. Induction by NblR is strongly dependent on DNA sequences located at least 44 bp upstream transcription initiation from P(nblA-2), and is also hampered by point mutations at HLR1. Genetic evidence of the antagonistic roles of NblR and SipA at regulation of the nblA gene, chlorosis and survival from stress is presented.
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PMID:The regulatory factor SipA provides a link between NblS and NblR signal transduction pathways in the cyanobacterium Synechococcus sp. PCC 7942. 1800 83


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