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)

The activation of heterotrimeric G proteins induced by G protein coupled receptors (GPCR) is generally believed to occur by a GDP/GTP exchange at the G protein alpha -subunit. Nevertheless, nucleoside diphosphate kinase (NDPK) and the beta-subunit of G proteins (Gbeta) participate in G protein activation by phosphate transfer reactions leading to the formation of GTP from GDP. Recent work elucidated the role of these reactions. Apparently, the NDPK isoform B (NDPK B) forms a complex with Gbetagamma dimers in which NDPK B acts as a histidine kinase phosphorylating Gbeta at His266. Out of this high energetic phosphoamidate bond the phosphate can be transferred specifically onto GDP. The formed GTP binds to the G protein alpha-subunit and thus activates the respective G protein. Evidence is presented, that this process occurs independent of the classical GPCR-induced GTP/GTP exchange und thus contributes, e.g. to the regulation of basal cAMP synthesis in cells.
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PMID:High energy phosphate transfer by NDPK B/Gbetagammacomplexes--an alternative signaling pathway involved in the regulation of basal cAMP production. 1695 86

The Ca2+ -activated K+ channel KCa3.1 is required for Ca2+ influx and the subsequent activation of B and T cells. Inhibitors of KCa3.1 are in development to treat autoimmune diseases and transplant rejection, underscoring the importance in understanding how these channels are regulated. We show that nucleoside diphosphate kinase B (NDPK-B), a mammalian histidine kinase, functions downstream of PI(3)P to activate KCa3.1. NDPK-B directly binds and activates KCa3.1 by phosphorylating histidine 358 in the carboxyl terminus of KCa3.1. Endogenous NDPK-B is also critical for KCa3.1 channel activity and the subsequent activation of CD4 T cells. These findings provide one of the best examples whereby histidine phosphorylation regulates a biological process in mammals, and provide an example whereby a channel is regulated by histidine phosphorylation. The critical role for NDPK-B in the reactivation of CD4 T cells indicates that understanding NDPK-B regulation should uncover novel pathways required for T cell activation.
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PMID:Histidine phosphorylation of the potassium channel KCa3.1 by nucleoside diphosphate kinase B is required for activation of KCa3.1 and CD4 T cells. 1715 50

It is generally accepted that G protein coupled receptors (GPCR) activate heterotrimeric G proteins by inducing a GDP/GTP exchange at the G protein alpha subunit. In addition, the transfer of high energetic phosphate by nucleoside diphosphate kinase (NDPK) and/or the beta subunit of G proteins (Gbeta) can induce G protein activation. Recent evidence suggests that the NDPK isoform B (NDPK B) forms a complex with Gbetagamma dimers. In this complex, NDPK B acts as a protein histidine kinase phosphorylating Gbeta at histidine residue 266 (His266). The high energetic phosphoamidate bond on His266 allows for a phosphate transfer specifically onto GDP and thus local formation of GTP, which binds to and thereby activates the respective G protein alpha subunit. Apparently, this process occurs independent of the classical GPCR-induced GDP/GTP exchange at least for members of the G(s) and G(i) subfamilies of heterotrimeric G proteins. By using a mutant of Gbeta(1) in which His266 was replaced by Leu, it was recently demonstrated that NDPK B/Gbetagamma-mediated G(s) activation contributes by about 50% to basal cAMP formation and contractility in rat cardiac myocytes. Besides its apparent role in G protein activation, the complex formation of NDPK B with Gbetagamma dimers might be essential for G protein stability. Depletion of either the NDPK B orthologue or Gbeta(1) isoforms in zebrafish embryos led to a similar phenotype displaying contractile dysfunction in the heart accompanied by a complete loss of heterotrimeric G protein expression. In conclusion, the interaction of NDKP B with Gbetagamma dimers might play an important role in signal transduction, and alterations in this novel pathway might be of pathophysiological importance.
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PMID:Interaction of nucleoside diphosphate kinase B with heterotrimeric G protein betagamma dimers: consequences on G protein activation and stability. 1720 Aug 62

The Bacillus subtilis histidine kinase KinA controls activation of the transcription factor governing sporulation, Spo0A. The decision to sporulate involves KinA phosphorylating itself on a conserved histidine residue, after which the phosphate moiety is relayed via two other proteins to Spo0A. The DNA-damage checkpoint inhibitor Sda halts this pathway by binding KinA and blocking the autokinase reaction. We have performed small-angle X-ray scattering and neutron contrast variation studies on the complex formed by KinA and Sda. The data show that two Sda molecules bind to the base of the DHp dimerization domain of the KinA dimer. In this position Sda does not appear to be able to sterically block the catalytic domain from accessing its target histidine, as previously proposed, but rather may effect an allosteric mode of inhibition involving transmission of the inhibitory signal via the four-helix bundle that forms the DHp domain.
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PMID:The structure of the KinA-Sda complex suggests an allosteric mechanism of histidine kinase inhibition. 1735 39

Liver regeneration (LR) is a process during which the liver recovers its mass and function after damage due to various causes such as partial hepatectomy (PH). It involves a sequence of well-orchestrated changes in physiological and biochemical activities, especially in the gene expression profile in a variety of liver cells. In order to produce reliable gene expression of target genes in eight kinds of rat hepatic cells during LR, the determination of internal control housekeeping genes (HKGs) is required. Eight kinds of hepatic cells were first isolated from liver tissue with high purity and activity. Then quantitative real-time reverse transcription (RT)-PCR was applied to detect expression changes of six commonly used HKGs (18SrRNA, B2M, ACTB, UBC, GAPDH, and HK1) in eight types of hepatic cells isolated from regenerating liver at 0, 2, 6, 12, 24, 30, 36, 72, 120, and 168 h after PH. The amplification of the HKGs was statistically analyzed by using geNorm algorithm. Using this method, 18SrRNA-UBC, ACTB-HK1, ACTB-GADPH, B2M-ACTB, 18SrRNA-UBC, B2M-UBC, B2M-ACTB, and B2M-UBC were found to be the two most stable reference genes for rat regenerating hepatocytes, hepatic stellate cells, Kupffer cells, biliary epithelial cells, sinusoidal endothelial cells, pit cells, dendritic cells, and oval cells, respectively, regardless of the stages of LR. In conclusion, this study has laid a good foundation for investigating gene expression of target genes in different types of hepatic cells during LR.
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PMID:Reference gene selection for real-time RT-PCR in eight kinds of rat regenerating hepatic cells. 2033 55

NDK (nucleoside diphosphate kinase) is primarily involved in maintaining cellular nucleotide pools in both prokaryotes and eukaryotes. We cloned ndk from Salmonella typhimurium and expressed it in Escherichia coli as a histidine-tagged protein. The Ni-NTA (Ni(2+)-nitrilotriacetate)-purified protein (sNDK) was found to be tetrameric with a monomeric unit molecular mass of approximately 18 kDa. The sNDK exhibited bivalent-cation-dependent autophosphorylation at a wide range of pH values and the phosphorylation withstands acid or alkali treatment. Surprisingly, nucleoside diphosphates did not behave as 'true inhibitors' of autophosphorylation activity. The sNDK displayed phosphotransfer activity from nucleoside triphosphates to nucleoside diphosphates; however, it was Mg(2+)/Mn(2+)-dependent. Mutational analysis established His(117) as the predominantly phosphorylating residue in sNDK. Although it is a histidine kinase, we found that substitution of Ser(119) with alanine/glutamate significantly affected the autophosphorylation, as well as the NTP-synthesizing ability of sNDK. Interestingly, the mixture of inactive (H117A) and partially active (S119A) proteins was found to be catalytically more efficient than the presence of corresponding amounts of active population, advocating transfer of phosphate from phospho-His(117) to Ser(119). Consistent with this observation, the Ni-NTA-purified H117A protein, obtained following co-expression of both of the mutant constructs [His-tagged H117A and GST (glutathione transferase)-tagged S119A] in E. coli, exhibited autophosphorylation, thereby alluding to intermolecular phosphotransfer between His(117) and Ser(119). Although this housekeeping enzyme has long been discovered and characterized from different sources, the results of the present study portray how Ser(119) in sNDK is phosphorylated. Furthermore, our findings illustrate for the first time that the intermolecular phosphotransfer is mandatory for the efficient NTP synthesis in any NDK.
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PMID:Intermolecular phosphotransfer is crucial for efficient catalytic activity of nucleoside diphosphate kinase. 2057 62

Highly proliferating cells, normal or transformed, undergo aerobic glycolysis whereby glucose is metabolized to lactate rather than by oxidative metabolism, even in the presence of oxygen. This metabolic adaptation provides a survival advantage and facilitates synthesis of biosynthetic precursors required for continued cellular proliferation. An important mediator of aerobic glycolysis is our demonstration that in malignant gliomas there is over-expression of the glycolytic enzyme hexokinase 2 (HK2), phosphorylating glucose as the first step of the glycolytic pathway. In contrast, normal brain preferentially expresses HK1 and undergoes oxidative glucose metabolism. In this study, we examine whether this switch in HK isoform also occurs in the developing embryo and central nervous system (CNS). Bioinformatic analysis of available microarray data, including that of The Cancer Genome Atlas, demonstrated a ~17% overlap in metabolic-related genes in blastocyst stage embryo and human GBM tissue, including upregulation of HK2 and downregulation of HK1. Quantitative RT-PCR on mouse brains isolated at different embryonic and postnatal development time-points demonstrated HK2 expression was highest in the early embryo, while HK1 expression increased with CNS maturation. The downstream glycolytic enzymes PKM2 and LDHA had similar temporal profiles as HK2. Expression of the HK2 isoform was due in part to epigenetic regulation of HK2. In support, adult normal human brain and the few human GBM cell lines with low HK2 expression had methylation of CpG islands within intron 1 of HK2. In contrast, developing human fetal brain and GBM tissue expressing HK2 demonstrated significantly lower percent methylation. Furthermore, treatment of GBM cells lacking HK2 with 5-aza-2-deoxycytidine restored HK2 transcript expression. Overall, our results demonstrate that proliferative states including the developing embryo and malignant gliomas, which rely on aerobic glycolysis, preferentially express the HK2 isoform, found to be regulated in part epigenetically.
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PMID:Developmental profile and regulation of the glycolytic enzyme hexokinase 2 in normal brain and glioblastoma multiforme. 2172 46

Reversible protein phosphorylation is the most widespread regulatory mechanism in signal transduction. Autophosphorylation in a dimeric sensor histidine kinase is the first step in two-component signalling, the predominant signal-transduction device in bacteria. Despite being the most abundant sensor kinases in nature, the molecular bases of the histidine kinase autophosphorylation mechanism are still unknown. Furthermore, it has been demonstrated that autophosphorylation can occur in two directions, cis (intrasubunit) or trans (intersubunit) within the dimeric histidine kinase. Here, we present the crystal structure of the complete catalytic machinery of a chimeric histidine kinase. The structure shows an asymmetric histidine kinase dimer where one subunit is caught performing the autophosphorylation reaction. A structure-guided functional analysis on HK853 and EnvZ, two prototypical cis- and trans-phosphorylating histidine kinases, has allowed us to decipher the catalytic mechanism of histidine kinase autophosphorylation, which seems to be common independently of the reaction directionality.
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PMID:Visualizing autophosphorylation in histidine kinases. 2450 Feb 24

The directional transport of auxin, known as polar auxin transport (PAT), allows asymmetric distribution of this hormone in different cells and tissues. This system creates local auxin maxima, minima, and gradients that are instrumental in both organ initiation and shape determination. As such, PAT is crucial for all aspects of plant development but also for environmental interaction, notably in shaping plant architecture to its environment. Cell to cell auxin transport is mediated by a network of auxin carriers that are regulated at the transcriptional and post-translational levels. Here we review our current knowledge on some aspects of the 'non-genomic' regulation of auxin transport, placing an emphasis on how phosphorylation by protein and lipid kinases controls the polarity, intracellular trafficking, stability, and activity of auxin carriers. We describe the role of several AGC kinases, including PINOID, D6PK, and the blue light photoreceptor phot1, in phosphorylating auxin carriers from the PIN and ABCB families. We also highlight the function of some receptor-like kinases (RLKs) and two-component histidine kinase receptors in PAT, noting that there are probably RLKs involved in co-ordinating auxin distribution yet to be discovered. In addition, we describe the emerging role of phospholipid phosphorylation in polarity establishment and intracellular trafficking of PIN proteins. We outline these various phosphorylation mechanisms in the context of primary and lateral root development, leaf cell shape acquisition, as well as root gravitropism and shoot phototropism.
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PMID:Regulation of polar auxin transport by protein and lipid kinases. 2724 71

Reversible phosphorylation is a key mechanism that regulates many cellular processes in prokaryotes and eukaryotes. In prokaryotes, signal transduction includes two-component signaling systems, which involve a membrane sensor histidine kinase and a cognate DNA-binding response regulator. Several recent studies indicate that alternative regulatory pathways controlled by Hanks-type serine/threonine kinases (STKs) and serine/threonine phosphatases (STPs) also play an essential role in regulation of many different processes in bacteria, such as growth and cell division, cell wall biosynthesis, sporulation, biofilm formation, stress response, metabolic and developmental processes, as well as interactions (either pathogenic or symbiotic) with higher host organisms. Since these enzymes are not DNA-binding proteins, they exert the regulatory role via post-translational modifications of their protein targets. In this review, we summarize the current knowledge of STKs and STPs, and discuss how these enzymes mediate gene expression in prokaryotes. Many studies indicate that regulatory systems based on Hanks-type STKs and STPs play an essential role in the regulation of various cellular processes, by reversibly phosphorylating many protein targets, among them several regulatory proteins of other signaling cascades. These data show high complexity of bacterial regulatory network, in which the crosstalk between STK/STP signaling enzymes, components of TCSs, and the translational machinery occurs. In this regulation, the STK/STP systems have been proved to play important roles.
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PMID:Hanks-Type Serine/Threonine Protein Kinases and Phosphatases in Bacteria: Roles in Signaling and Adaptation to Various Environments. 3024 37


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