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)

Histidine kinases allow bacteria, plants, and fungi to sense and respond to their environment. The 2.6 A resolution crystal structure of Thermotoga maritima CheA (290-671) histidine kinase reveals a dimer where the functions of dimerization, ATP binding, and regulation are segregated into domains. The kinase domain is unlike Ser/Thr/Tyr kinases but resembles two ATPases, Gyrase B and Hsp90. Structural analogies within this superfamily suggest that the P1 domain of CheA provides the nucleophilic histidine and activating glutamate for phosphotransfer. The regulatory domain, which binds the homologous receptor-coupling protein CheW, topologically resembles two SH3 domains and provides different protein recognition surfaces at each end. The dimerization domain forms a central four-helix bundle about which the kinase and regulatory domains pivot on conserved hinges to modulate transphosphorylation. Different subunit conformations suggest that relative domain motions link receptor response to kinase activity.
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PMID:Structure of CheA, a signal-transducing histidine kinase. 998 4

In Candida albicans, three putative histidine kinase genes have been described thus far, including CaSLN1, CaNIK1/COS1 and CaHK1. The encoded proteins for C. albicans, CaSln1p and CaNik1p, which are similar to Sln1p from Saccharomyces cerevisiae and Nik-1 from Neurospora crassa, seem to function in osmoregulation and morphogenesis, respectively. Recently, the isolation of CaHK1, a putative histidine kinase gene from C. albicans has been reported. In addition to the histidine and aspartyl domains located at its C-terminus as previously described, it is shown here that the N-terminal domain of Cahk1p contains a P-loop motif and a sequence which shows significant homology with the seven C-terminal domains of serine/threonine kinases. The Ser/Thr-homologous domains of Cahk1p could, in fact, correspond to its sensor sequence. CaHK1 has been mapped to chromosome 2 and gene deletion studies were undertaken to understand its function. Deltacahk1 mutants are phenotypically different from any other histidine kinase mutants thus far described either in C. albicans or in any other yeast or filamentous fungus. This study demonstrates that deltacahk1 mutants flocculate extensively in a gene-dosage-dependent manner under conditions which induce germ-tube formation, such as growth in medium 199 (pH 7.5). The flocculation occurs by an interaction along the hyphal surfaces, probably because of the altered expression of one or more hyphal-cell-surface components in the deltacahk1 mutants. These results indicate that CaHK1 could be involved in regulating their expression.
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PMID:Flocculation of hyphae is associated with a deletion in the putative CaHK1 two-component histidine kinase gene from Candida albicans. 1041 Dec 70

The histidine kinase/phosphatase EnvZ helps Escherichia coli adapt to osmotic shock by controlling the phosphorylation state of the transcription factor OmpR, which regulates the levels of the outer membrane porin proteins OmpF and OmpC. We examined the effects of mutating the highly conserved Thr(247) residue in EnvZ. Using purified C-terminal domains of wild-type and mutant EnvZ proteins, we demonstrate that Thr(247) plays a vital role in EnvZ function, variously affecting its autokinase and phosphotransferase activities, but mostly its function as a phosphatase. The cytoplasmic domain of EnvZ (EnvZc) is composed of three segments: the linker domain (residues 180-222), domain A (residues 223-289), and domain B (residues 290-450). It has been shown that the isolated domain A itself can dephosphorylate phosphorylated OmpR. Here we show that mutating Thr(247) to Arg in domain A abolishes its phosphatase activity. Furthermore, using an in vivo beta-galactosidase activity assay of Taz1-1 (hybrid of the aspartate receptor Tar and EnvZ) constructs of the Thr(247) mutants in RU1012 cells expressing ompC-lacZ, we demonstrate that the external signal primarily down-regulates the phosphatase activity of EnvZ. Of the nine EnvZc(T247X) mutants (X = Ser, Ala, Cys, Lys, Asn, Glu, Gln, Tyr, or Arg) analyzed, only Ser functionally substituted for Thr at this position, whereas all the others displayed constitutive expression of beta-galactosidase.
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PMID:The critical role of the conserved Thr247 residue in the functioning of the osmosensor EnvZ, a histidine Kinase/Phosphatase, in Escherichia coli. 1097 66

Using insulin-secreting cells, we previously demonstrated that specific proteins associated with the cytosolic, secretory granule, and mitochondrial fractions undergo a novel type of phosphorylation on their histidine residues. Subsequently, we identified these proteins as the nucleoside diphosphate kinase (NDPK) [Kowluru and Metz, Biochemistry 1994;33:12495-503], the beta subunit of trimeric GTP-binding proteins [Kowluru et al., Biochem J 1996;313:97-107], and the alpha subunit of succinyl-CoA synthetase [Kowluru, Diabetologia 2001;44:89-94], respectively. Since several other enzymes of intermediary metabolism (e.g. ATP-citrate lyase and glucose-6-phosphatase) also undergo histidine phosphorylation, these initial findings may have a more generalized significance to beta cells. Herein, we characterized a novel protein histidine kinase in pancreatic beta cells, and determined it to be acid- and heat-labile as well as alkali-resistant in its phosphorylation of histone 4. Such an activity was detected in normal rat islets, human islets, and clonal beta (HIT-T15 and INS-1) cells, and could utilize either ATP or GTP as a phosphoryl donor (with K(m) values in the range of 60-100 microM). On a size-exclusion column, its molecular mass was estimated to be in the range of 60-70 kDa. It was stimulated by divalent cations (Mg(2+)>Mn(2+)>control=Ca(2+)=Zn(2+)=Co(2+)), but was resistant to polyamines. It was inactivated by known in vitro inhibitors of protein histidine phosphorylation (e.g. UDP or cromoglycate). Mastoparan, a global activator of G-proteins and insulin secretion from isolated beta cells, but not mastoparan-17, its inactive analog, stimulated histidine kinase activity and histidine phosphorylation of G(beta) subunit and insulin secretion from isolated rat islets. These studies identify, for the first time, a protein kinase activity in the pancreatic beta cell that does not act on traditional -Ser, -Tyr, or -Thr residues. They also establish a possible link between histidine kinase activity and G(beta) phosphorylation in isolated beta cells.
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PMID:Identification and characterization of a novel protein histidine kinase in the islet beta cell: evidence for its regulation by mastoparan, an activator of G-proteins and insulin secretion. 1211 Mar 68

A histidine kinase-based signaling system has been proposed to function in ethylene signal transduction pathway of plants and one ethylene receptor has been found to possess His kinase activity. Here we demonstrate that a His kinase-like ethylene receptor homologue NTHK1 from tobacco has serine/threonine (Ser/Thr) kinase activity, but no His kinase activity. Evidence obtained by analyzing acid/base stability, phosphoamino acid and substrate specificity of the phosphorylated kinase domain, supports this conclusion. In addition, mutation of the presumptive phosphorylation site His (H378) to Gln did not affect the kinase activity whereas deletion of the ATP-binding domain eliminated it, indicating that the conserved His (H378) is not required for the kinase activity and this activity is intrinsic to the NTHK1-KD. Moreover, confocal analysis of NTHK1 expression in insect cells and plant cells suggested the plasma membrane localization of the NTHK1 protein. Thus, NTHK1 may represent a distinct Ser/Thr kinase-type ethylene receptor and function in an alternative mechanism for ethylene signal transduction.
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PMID:Serine/threonine kinase activity in the putative histidine kinase-like ethylene receptor NTHK1 from tobacco. 1253 51

Protein phosphorylation is a vital process in the regulation of mammalian cell division and the protein kinases that catalyze the phosphorylation of proteins on serine, threonine and tyrosine residues have been well characterized. In contrast, little is known about the kinases involved in protein histidine phosphorylation, which have been described in various mammalian cells that are highly proliferative. Histone H4 histidine kinase (HHK) activity is highly active in regenerating rat liver. Using a novel and specific assay, we demonstrate that it is active in human fetal liver, essentially absent in adult liver and highly expressed in liver tumours. 'Normal' liver surrounding the HCC contains low to undetectable levels of HHK. In a rodent model of chronic liver injury that leads to HCC, its activity is induced. Two lines of evidence suggest that liver progenitor (oval) cells, which populate the liver at early stages following induction of liver damage are responsible for the increased activity. Purified oval cells, as well as cell lines established from primary cultures of oval cells express high levels of HHK. We propose that the pattern of expression of histone H4 histidine kinase activity justifies its classification as an oncodevelopmental marker and suggest it may be useful as a diagnostic marker for hepatocellular carcinoma as well for identifying preneoplastic lesions.
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PMID:Histone H4 histidine kinase displays the expression pattern of a liver oncodevelopmental marker. 1524 May 7

Protein phosphorylation is one of the most ubiquitous and important types of post-translational modification for the regulation of cell function. The importance of two-component histidine kinases in bacteria, fungi and plants has long been recognised. In mammals, the regulatory roles of serine/threonine and tyrosine kinases have attracted most attention. However, the existence of histidine kinases in mammalian cells has been known for many years, although little is still understood about their biological roles by comparison with the hydroxyamino acid kinases. In addition, with the exception of NDP kinase, other mammalian histidine kinases remain to be identified and characterised. NDP kinase is a multifunctional enzyme that appears to act as a protein histidine kinase and as such, to regulate the activation of some G-proteins. Histone H4 histidine kinase activity has been shown to correlate with cellular proliferation and there is evidence that it is an oncodevelopmental marker in liver. This review mainly concentrates on describing recent research on these two types of histidine kinase. Developments in methods for the detection and assay of histidine kinases, including mass spectrometric methods for the detection of phosphohistidines in proteins and in-gel kinase assays for histone H4 histidine kinases, are described. Little is known about inhibitors of mammalian histidine kinases, although there is much interest in two-component histidine kinase inhibitors as potential antibiotics. The inhibition of a histone H4 histidine kinase by genistein is described and that of two-component histidine kinase inhibitors of structurally-related mammalian protein kinases. In addition, recent findings concerning mammalian protein histidine phosphatases are briefly described.
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PMID:Mammalian histidine kinases. 1618 7

Adaptation to an environmental stress is essential for cell survival in all organisms, from E. coli to human. To respond to changes in their surroundings, bacteria utilize two-component systems (TCSs), also known as histidyl-aspartyl phosphorelay (HAP) systems that consist of a histidine kinase (HK) sensor and a cognate response regulator (RR). While mammals developed complex signaling systems involving serine/threonine/tyrosine kinases in stress response mechanisms, bacterial TCS/HAP systems represent a simple but elegant prototype of signal transduction machineries. HKs are known as a seductive target for anti-bacterial therapeutic development, because of their significance in pathological virulence in some bacteria such as Salmonella enterica. Recent molecular and structural studies have shed light on the molecular basis of the signaling mechanism of HK sensor kinases. This review will focus on recent advancements in structural investigation of signal sensing and transducing mechanisms by HKs, which is critical to our understanding of bacterial biology and pathology.
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PMID:Bacterial histidine kinase as signal sensor and transducer. 1624 88

Bacterial histidine kinases have been proposed as targets for the discovery of new antibiotics, yet few specific inhibitors of bacterial histidine kinases have been reported. We report here a novel thienopyridine (TEP) compound that inhibits bacterial histidine kinases competitively with respect to ATP but does not comparably inhibit mammalian serine/threonine kinases. Although it partitions into membranes and does not inhibit the growth of bacterial or mammalian cells, TEP could serve as a starting compound for a new class of histidine kinase inhibitors with antibacterial activity.
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PMID:New class of competitive inhibitor of bacterial histidine kinases. 1629 94

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


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