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)

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.
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PMID:Defective hyphal development and avirulence caused by a deletion of the SSK1 response regulator gene in Candida albicans. 1063 12

Ssk1p of Candida albicans is a putative response regulator protein of the Hog1 two-component signal transduction system. In Saccharomyces cerevisiae, the phosphorylation state of Ssk1p determines whether genes that promote the adaptation of cells to osmotic stress are activated. We have previously shown that C. albicans SSK1 does not complement the ssk1 mutant of S. cerevisiae and that the ssk1 mutant of C. albicans is not sensitive to sorbitol. In this study, we show that the C. albicans ssk1 mutant is sensitive to several oxidants, including hydrogen peroxide, t-butyl hydroperoxide, menadione, and potassium superoxide when each is incorporated in yeast extract-peptone-dextrose (YPD) agar medium. We used DNA microarrays to identify genes whose regulation is affected by the ssk1 mutation. RNA from mutant cells (strain CSSK21) grown in YPD medium for 3 h at 30 degrees C was reverse transcribed and then compared with similarly prepared RNA from wild-type cells (CAF2). We observed seven genes from mutant cells that were consistently up regulated (three-fold or greater compared to CAF2). In S. cerevisiae, three (AHP1, HSP12, and PYC2) of the seven genes that were up regulated provide cells with an adaptation function in response to oxidative stress; another gene (GPH1) is regulated under stress conditions by Hog1p. Three other genes that are up regulated encode a cell surface protein (FLO1), a mannosyl transferase (MNN4-4), and a putative two-component histidine kinase (CHK1) that regulates cell wall biosynthesis in C. albicans. Of the down-regulated genes, ALS1 is a known cell adhesin in C. albicans. Verification of the microarray data was obtained by reverse transcription-PCR for HSP12, AHP1, CHK1, PYC2, GPH1, ALS1, MNN4-4, and FLO1. To further determine the function of Ssk1p in the Hog1p signal transduction pathway in C. albicans, we used Western blot analysis to measure phosphorylation of Hog1p in the ssk1 mutant of C. albicans when grown under either osmotic or oxidative stress. We observed that Hog1p was phosphorylated in the ssk1 mutant of C. albicans when grown in a hyperosmotic medium but was not phosphorylated in the ssk1 mutant when the latter was grown in the presence of hydrogen peroxide. These data indicate that C. albicans utilizes the Ssk1p response regulator protein to adapt cells to oxidative stress, while its role in the adaptation to osmotic stress is less certain. Further, SSK1 appears to have a regulatory function in some aspects of cell wall biosynthesis. Thus, the functions of C. albicans SSK1 differ from those of S. cerevisiae SSK1.
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PMID:Candida albicans response regulator gene SSK1 regulates a subset of genes whose functions are associated with cell wall biosynthesis and adaptation to oxidative stress. 1455 84

In Saccharomyces cerevisiae, a branched multistep phosphorelay signaling pathway regulates cellular adaptation to hyperosmotic stress. YPD1 functions as a histidine-phosphorylated protein intermediate required for phosphoryl group transfer from a membrane-bound sensor histidine kinase (SLN1) to two distinct response regulator proteins (SSK1 and SKN7). These four proteins are evolutionarily related to the well-characterized "two-component" regulatory proteins from bacteria. Although structural information is available for many two-component signaling proteins, there are very few examples of complexes between interacting phosphorelay partners. Here we report the first crystal structure of a prototypical monomeric histidine-containing phosphotransfer (HPt) protein YPD1 in complex with its upstream phosphodonor, the response regulator domain associated with SLN1.
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PMID:The yeast YPD1/SLN1 complex: insights into molecular recognition in two-component signaling systems. 1465 27

The two-component histidine kinase Chk1p of Candida albicans has been implicated in the regulation of cell wall biosynthesis. Deletion of CHK1 results in avirulence that in part may be due to the increased sensitivity of mutant strains to polymorphonuclear leukocytes. The mutant also does not adhere to human oesophageal tissue in vitro, probably as a consequence of its altered cell wall. In the current study, a CHK1 promoter-lacZ reporter (CHK1prlacZ) construct was expressed in wild-type C. albicans strain CAI4 and in two-component signal transduction mutants to determine the effect of environmental stress conditions on the regulation of CHK1 and the co-regulatory activities among these proteins. It is shown that lacZ expression varied according to the type of growth conditions and incubation time; expression was also influenced by the strain background. lacZ expression in CAI4 was greater at 37 degrees C and at a pH of 3.5 and in the presence of 4 mM H2O2, 0.1 mM menadione, 10 % serum or 1.5 M NaCl compared to cells grown at 30 or 42 degrees C. The increases in expression were time-dependent and not observed until cells were incubated for 120 min in these conditions (P < 0.05). As a correlate of the increase in transcription of CHK1-lacZ in the presence of H2O2, the chk1 mutant was more sensitive than wild-type and revertant cells to H2O2 in vitro. In addition to strain CAI4, we also measured CHK1p-lacZ reporter activity of mutants deleted in genes encoding other two-component proteins such as the response regulator gene SSK1, the histidine kinases, SLN1 and NIK1, and the HOG1 MAP kinase. Of these proteins, Ssk1p and Sln1p are presumed to mediate phosphotransfer to the HOG1 [hyperosmotic glycerol] MAP kinase pathway during oxidative and perhaps osmotic stress in C. albicans. Compared to strain CAI4, lacZ reporter activity increased significantly in the ssk1 mutant under all growth conditions after a 10 and 120 min incubation (P < 0.0001). lacZ expression in the ssk1 mutant was less at 42 degrees C compared to all other growth conditions (P < 0.05). Furthermore, lacZ reporter activity also increased in the hog1 mutant of C. albicans. These data suggest that SSK1 and HOG1 indirectly or directly negatively regulate CHK1 under most growth conditions tested. In the sln1 mutant, downregulation of CHK1 was observed in all growth conditions compared to strain CAI4 (P < 0.05), while regulation of lacZ in the nik1 mutant was similar to strain CAI4 except when cells were incubated in the presence of 4 mM H2O2 for 120 min (P < 0.05). Western blot analysis was used to determine the role of Chk1p in phosphorylation of Hog1p under oxidative or osmotic stress. It was found that Hog1p was phosphorylated in the chk1 mutant similar to wild-type CAF2-1 cells, although the temporal events of phosphorylation differed slightly in mutant cells. These results show that transcription of CHK1, as measured by the lacZ reporter assay, is statistically increased when cells are exposed to several types of stress or when incubated in 10 % serum in a mutant-specific background and at a specific time point. Of importance, our data also suggest that lacZ expression is indirectly or directly regulated by the HOG1 MAP kinase pathway, although a determination of its position in this pathway or in a cross-talking pathway awaits additional studies.
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PMID:Studies on the regulation of the two-component histidine kinase gene CHK1 in Candida albicans using the heterologous lacZ reporter gene. 1547 Jan 10

We recently characterized the histidine kinase receptor genes of Candida lusitaniae. For the present study, we have further investigated the role of SSK1 and SKN7, encoding response regulators. The results of functional analysis of mutants indicated that Ssk1p is involved in osmotolerance and pseudohyphal development, whereas Skn7p appears crucial for oxidative stress adaptation.
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PMID:Contributions of the response regulators Ssk1p and Skn7p in the pseudohyphal development, stress adaptation, and drug sensitivity of the opportunistic yeast Candida lusitaniae. 1840 54

The multistep His-Asp phosphorelay system in Saccharomyces cerevisiae allows cells to adapt to osmotic, oxidative, and other environmental stresses. The pathway consists of a hybrid histidine kinase SLN1, a histidine-containing phosphotransfer (HPt) protein YPD1, and two response regulator proteins, SSK1 and SKN7. Under nonosmotic stress conditions, the SLN1 sensor kinase is active, and phosphoryl groups are shuttled through YPD1 to SSK1, therefore maintaining the response regulator protein in a constitutively phosphorylated state. The cellular response to hyperosmotic stress involves rapid efflux of water and changes in intracellular ion and osmolyte concentration. In this study, we examined the individual and combined effects of NaCl and glycerol on phosphotransfer rates within the SLN1-YPD1-SSK1 phosphorelay. The results show that the combined effects of glycerol and NaCl on the phosphotransfer reaction rates are different from the individual effects of glycerol and NaCl. The combinatory effect is likely more representative of the in vivo changes that occur during hyperosmotic stress. In addition, the effect of osmolyte concentration on the half-life of the phosphorylated SSK1 receiver domain in the presence/absence of YPD1 was evaluated. Our findings demonstrate that increasing osmolyte concentrations negatively affect the YPD1 x SSK1-P interaction, thereby facilitating dephosphorylation of SSK1 and activating the HOG1 MAP kinase cascade. In contrast, at the highest osmolyte concentrations, reflective of the osmoadaptation phase of the signaling pathway, the kinetics of the phosphorelay favor production of SSK1-P and inhibition of the HOG1 pathway.
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PMID:Effects of osmolytes on the SLN1-YPD1-SSK1 phosphorelay system from Saccharomyces cerevisiae. 1961 14

The tangerine pathotype of Alternaria alternata is a necrotrophic fungal pathogen causing brown spot disease on a number of citrus cultivars. To better understand the dynamics of signal regulation leading to oxidative and osmotic stress response and fungal infection on citrus, phenotypic characterization of the yeast SSK1 response regulator homolog was performed. It was determined that SSK1 responds to diverse environmental stimuli and plays a critical role in fungal pathogenesis. Experiments to determine the phenotypes resulting from the loss of SSK1 reveal that the SSK1 gene product may be fulfilling similar regulatory roles in signaling pathways involving a HOG1 MAP kinase during ROS resistance, osmotic resistance, fungicide sensitivity and fungal virulence. The SSK1 mutants display elevated sensitivity to oxidants, fail to detoxify H2O2 effectively, induce minor necrosis on susceptible citrus leaves, and displays resistance to dicarboximide and phenylpyrrole fungicides. Unlike the SKN7 response regulator, SSK1 and HOG1 confer resistance to salt-induced osmotic stress via an unknown kinase sensor rather than the "two component" histidine kinase HSK1. SSK1 and HOG1 play a moderate role in sugar-induced osmotic stress. We also show that SSK1 mutants are impaired in their ability to produce germ tubes from conidia, indicating a role for the gene product in cell differentiation. SSK1 also is involved in multi-drug resistance. However, deletion of the yeast SHO1 (synthetic high osmolarity) homolog resulted in no noticeable phenotypes. Nonetheless, our results show that A. alternata can sense and react to different types of stress via SSK1, HOG1 and SKN7 in a cooperative manner leading to proper physiological and pathological functions.
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PMID:How the Pathogenic Fungus Alternaria alternata Copes with Stress via the Response Regulators SSK1 and SHO1. 2686 27

Signaling systems allow microorganisms to sense and respond to different stimuli through the modification of gene expression. The phosphorelay signal transduction system in eukaryotes involves three proteins: a sensor protein, an intermediate protein and a response regulator, and requires the transfer of a phosphate group between two histidine-aspartic residues. The SLN1-YPD1-SSK1 system enables yeast to adapt to hyperosmotic stress through the activation of the HOG1-MAPK pathway. The genetic sequences available from Saccharomyces cerevisiae were used to identify orthologous sequences in Candida glabrata, and putative genes were identified and characterized by in silico assays. An interactome analysis was carried out with the complete genome of C. glabrata and the putative proteins of the phosphorelay signal transduction system. Next, we modeled the complex formed between the sensor protein CgSln1p and the intermediate CgYpd1p. Finally, phosphate transfer was examined by a molecular dynamic assay. Our in silico analysis showed that the putative proteins of the C. glabrata phosphorelay signal transduction system present the functional domains of histidine kinase, a downstream response regulator protein, and an intermediate histidine phosphotransfer protein. All the sequences are phylogenetically more related to S. cerevisiae than to C. albicans. The interactome suggests that the C. glabrata phosphorelay signal transduction system interacts with different proteins that regulate cell wall biosynthesis and responds to oxidative and osmotic stress the same way as similar systems in S. cerevisiae and C. albicans. Molecular dynamics simulations showed complex formation between the response regulator domain of histidine kinase CgSln1 and intermediate protein CgYpd1 in the presence of a phosphate group and interactions between the aspartic residue and the histidine residue. Overall, our research showed that C. glabrata harbors a functional SLN1-YPD1-SSK1 phosphorelay system.
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PMID:The phosphorelay signal transduction system in Candida glabrata: an in silico analysis. 2924 94

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