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Structure and Function of the Transmembrane Domain of NsaS, an Antibiotic Sensing Histidine Kinase in Staphylococcus aureus.
Bhate MP, Lemmin T, Kuenze G, Mensa B, Ganguly S, Peters JM, Schmidt N, Pelton JG, Gross CA, Meiler J, DeGrado WF
(2018) J Am Chem Soc 140: 7471-7485
MeSH Terms: Anti-Bacterial Agents, Bacitracin, Bacterial Proteins, Gene Knockout Techniques, Histidine Kinase, Hydrophobic and Hydrophilic Interactions, Magnetic Resonance Spectroscopy, Membrane Proteins, Microbial Sensitivity Tests, Molecular Dynamics Simulation, Nisin, Protein Conformation, alpha-Helical, Protein Domains, Staphylococcus aureus
Show Abstract · Added March 21, 2020
NsaS is one of four intramembrane histidine kinases (HKs) in Staphylococcus aureus that mediate the pathogen's response to membrane active antimicrobials and human innate immunity. We describe the first integrative structural study of NsaS using a combination of solution state NMR spectroscopy, chemical-cross-linking, molecular modeling and dynamics. Three key structural features emerge: First, NsaS has a short N-terminal amphiphilic helix that anchors its transmembrane (TM) bundle into the inner leaflet of the membrane such that it might sense neighboring proteins or membrane deformations. Second, the transmembrane domain of NsaS is a 4-helix bundle with significant dynamics and structural deformations at the membrane interface. Third, the intracellular linker connecting the TM domain to the cytoplasmic catalytic domains of NsaS is a marginally stable helical dimer, with one state likely to be a coiled-coil. Data from chemical shifts, heteronuclear NOE, H/D exchange measurements and molecular modeling suggest that this linker might adopt different conformations during antibiotic induced signaling.
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The Response of Acinetobacter baumannii to Zinc Starvation.
Nairn BL, Lonergan ZR, Wang J, Braymer JJ, Zhang Y, Calcutt MW, Lisher JP, Gilston BA, Chazin WJ, de Crécy-Lagard V, Giedroc DP, Skaar EP
(2016) Cell Host Microbe 19: 826-36
MeSH Terms: Acinetobacter Infections, Acinetobacter baumannii, Animals, Bacterial Proteins, Chlorides, GTP Phosphohydrolases, Gene Expression Regulation, Bacterial, Genes, Bacterial, Histidine, Histidine Ammonia-Lyase, Metallochaperones, Mice, Mice, Inbred C57BL, Mutation, Zinc, Zinc Compounds
Show Abstract · Added April 8, 2017
Zinc (Zn) is an essential metal that vertebrates sequester from pathogens to protect against infection. Investigating the opportunistic pathogen Acinetobacter baumannii's response to Zn starvation, we identified a putative Zn metallochaperone, ZigA, which binds Zn and is required for bacterial growth under Zn-limiting conditions and for disseminated infection in mice. ZigA is encoded adjacent to the histidine (His) utilization (Hut) system. The His ammonia-lyase HutH binds Zn very tightly only in the presence of high His and makes Zn bioavailable through His catabolism. The released Zn enables A. baumannii to combat host-imposed Zn starvation. These results demonstrate that A. baumannii employs several mechanisms to ensure bioavailability of Zn during infection, with ZigA functioning predominately during Zn starvation, but HutH operating in both Zn-deplete and -replete conditions to mobilize a labile His-Zn pool.
Copyright © 2016 Elsevier Inc. All rights reserved.
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16 MeSH Terms
Genetic Evolution of a Helicobacter pylori Acid-Sensing Histidine Kinase and Gastric Disease.
Krishna U, Romero-Gallo J, Suarez G, Azah A, Krezel AM, Varga MG, Forsyth MH, Peek RM
(2016) J Infect Dis 214: 644-8
MeSH Terms: Achlorhydria, Acids, Animals, Bacterial Proteins, Evolution, Molecular, Gastritis, Gerbillinae, Helicobacter Infections, Helicobacter pylori, Histidine Kinase, Humans, Male, Mice, Inbred C57BL, Microbial Viability, Mutation, Missense
Show Abstract · Added April 6, 2017
Helicobacter pylori is the strongest risk factor for gastric adenocarcinoma, which develops within a hypochlorhydric environment. We sequentially isolated H. pylori (strain J99) from a patient who developed corpus-predominant gastritis and hypochlorhydia over a 6-year interval. Archival J99 survived significantly better under acidic conditions than recent J99 strains. H. pylori arsRS encodes a 2-component system critical for stress responses; recent J99 isolates harbored 2 nonsynonymous arsS mutations, and arsS inactivation abolished acid survival. In vivo, acid-resistant archival, but not recent J99, successfully colonized high-acid-secreting rodents. Thus, genetic evolution of arsS may influence progression to hypochlorhydia and gastric cancer.
© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.
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15 MeSH Terms
Loss of the histidine kinase DhkD results in mobile mounds during development of Dictyostelium discoideum.
Singleton CK, Xiong Y
(2013) PLoS One 8: e75618
MeSH Terms: 3',5'-Cyclic-AMP Phosphodiesterases, Cyclic AMP, Dictyostelium, Genome, Protozoan, Histidine Kinase, Phenotype, Protein Kinases, Protozoan Proteins
Show Abstract · Added March 7, 2014
BACKGROUND - Histidine kinases are receptors for sensing cellular and environmental signals, and in response to the appropriate cue they initiate phosphorelays that regulate the activity of response regulators. The Dictyostelium discoideum genome encodes 15 histidine kinases that function to regulate several processes during the multicellular developmental program, including the slug to culmination transition, osmoregulation, and spore differentiation. While there are many histidine kinases, there is only a single response regulator, RegA. Not surprisingly given the ubiquitous involvement of cAMP in numerous processes of development in Dictyostelium, RegA is a cAMP phosphodiesterase that is activated upon receiving phosphates through a phosphorelay. Hence, all of the histidine kinases characterized to date regulate developmental processes through modulating cAMP production. Here we investigate the function of the histidine kinase DhkD.
PRINCIPAL FINDINGS - The dhkD gene was disrupted, and the resulting cells when developed gave a novel phenotype. Upon aggregation, which occurred without streaming, the mounds were motile, a phenotype termed the pollywog stage. The pollywog phenotype was dependent on a functional RegA. After a period of random migration, the pollywogs attempted to form fingers but mostly generated aberrant structures with no tips. While prestalk and prespore cell differentiation occurred with normal timing, proper patterning did not occur. In contrast, wild type mounds are not motile, and the cAMP chemotactic movement of cells within the mound facilitates proper prestalk and prespore patterning, tip formation, and the vertical elongation of the mound into a finger.
CONCLUSIONS - We postulate that DhkD functions to ensure the proper cAMP distribution within mounds that in turn results in patterning, tip formation and the transition of mounds to fingers. In the absence of DhkD, aberrant cell movements in response to an altered cAMP distribution result in mound migration, a lack of proper patterning, and an inability to generate normal finger morphology.
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8 MeSH Terms
Molecular basis for manganese sequestration by calprotectin and roles in the innate immune response to invading bacterial pathogens.
Damo SM, Kehl-Fie TE, Sugitani N, Holt ME, Rathi S, Murphy WJ, Zhang Y, Betz C, Hench L, Fritz G, Skaar EP, Chazin WJ
(2013) Proc Natl Acad Sci U S A 110: 3841-6
MeSH Terms: Amino Acid Substitution, Binding Sites, Calgranulin A, Calgranulin B, Crystallography, X-Ray, Histidine, Host-Pathogen Interactions, Humans, Immunity, Innate, Leukocyte L1 Antigen Complex, Manganese, Models, Molecular, Mutagenesis, Site-Directed, Protein Multimerization, Recombinant Proteins, Staphylococcus aureus, Zinc
Show Abstract · Added March 7, 2014
The S100A8/S100A9 heterodimer calprotectin (CP) functions in the host response to pathogens through a mechanism termed "nutritional immunity." CP binds Mn(2+) and Zn(2+) with high affinity and starves bacteria of these essential nutrients. Combining biophysical, structural, and microbiological analysis, we identified the molecular basis of Mn(2+) sequestration. The asymmetry of the CP heterodimer creates a single Mn(2+)-binding site from six histidine residues, which distinguishes CP from all other Mn(2+)-binding proteins. Analysis of CP mutants with altered metal-binding properties revealed that, despite both Mn(2+) and Zn(2+) being essential metals, maximal growth inhibition of multiple bacterial pathogens requires Mn(2+) sequestration. These data establish the importance of Mn(2+) sequestration in defense against infection, explain the broad-spectrum antimicrobial activity of CP relative to other S100 proteins, and clarify the impact of metal depletion on the innate immune response to infection.
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Nature of KaiB-KaiC binding in the cyanobacterial circadian oscillator.
Pattanayek R, Yadagiri KK, Ohi MD, Egli M
(2013) Cell Cycle 12: 810-7
MeSH Terms: Bacterial Proteins, Circadian Clocks, Circadian Rhythm Signaling Peptides and Proteins, Histidine, Models, Molecular, Nanostructures, Negative Staining, Oligopeptides, Protein Binding, Scattering, Small Angle, Static Electricity, Synechococcus, X-Ray Diffraction
Show Abstract · Added March 7, 2014
In the cyanobacteria Synechococcus elongatus and Thermosynechococcus elongatus, the KaiA, KaiB and KaiC proteins in the presence of ATP generate a post-translational oscillator (PTO) that can be reconstituted in vitro. KaiC is the result of a gene duplication and resembles a double doughnut with N-terminal CI and C-terminal CII hexameric rings. Six ATPs are bound between subunits in both the CI and CII ring. CI harbors ATPase activity, and CII catalyzes phosphorylation and dephosphorylation at T432 and S431 with a ca. 24-h period. KaiA stimulates KaiC phosphorylation, and KaiB promotes KaiC subunit exchange and sequesters KaiA on the KaiB-KaiC interface in the final stage of the clock cycle. Studies of the PTO protein-protein interactions are convergent in terms of KaiA binding to CII but have led to two opposing models of the KaiB-KaiC interaction. Electron microscopy (EM) and small angle X-ray scattering (SAXS), together with native PAGE using full-length proteins and separate CI and CII rings, are consistent with binding of KaiB to CII. Conversely, NMR together with gel filtration chromatography and denatured PAGE using monomeric CI and CII domains support KaiB binding to CI. To resolve the existing controversy, we studied complexes between KaiB and gold-labeled, full-length KaiC with negative stain EM. The EM data clearly demonstrate that KaiB contacts the CII ring. Together with the outcomes of previous analyses, our work establishes that only CII participates in interactions with KaiA and KaiB as well as with the His kinase SasA involved in the clock output pathway.
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13 MeSH Terms
XZH-5 inhibits STAT3 phosphorylation and enhances the cytotoxicity of chemotherapeutic drugs in human breast and pancreatic cancer cells.
Liu A, Liu Y, Jin Z, Hu Q, Lin L, Jou D, Yang J, Xu Z, Wang H, Li C, Lin J
(2012) PLoS One 7: e46624
MeSH Terms: Animals, Apoptosis, Blotting, Western, Breast Neoplasms, Cell Line, Tumor, Cell Movement, Cyclin D1, Female, HeLa Cells, Histidine, Humans, Inhibitor of Apoptosis Proteins, Interleukin-6, Mice, Mice, SCID, Pancreatic Neoplasms, Phenylurea Compounds, Phosphorylation, Proto-Oncogene Proteins c-bcl-2, Reverse Transcriptase Polymerase Chain Reaction, STAT1 Transcription Factor, STAT3 Transcription Factor, Survivin
Show Abstract · Added June 14, 2013
Constitutive activation of Signal Transducers and Activators of Transcription 3 (STAT3) signaling is frequently detected in breast and pancreatic cancer. Inhibiting constitutive STAT3 signaling represents a promising molecular target for therapeutic approach. Using structure-based design, we developed a non-peptide cell-permeable, small molecule, termed as XZH-5, which targeted STAT3 phosphorylation. XZH-5 was found to inhibit STAT3 phosphorylation (Tyr705) and induce apoptosis in human breast and pancreatic cancer cell lines expressing elevated levels of phosphorylated STAT3. XZH-5 could also inhibit interleukin-6-induced STAT3 phosphorylation in cancer cell lines expressing low phosphorylated STAT3. Inhibition of STAT3 signaling by XZH-5 was confirmed by the down-regulation of downstream targets of STAT3, such as Cyclin D1, Bcl-2, and Survivin at mRNA level. In addition, XZH-5 inhibited colony formation, cell migration, and enhanced the cytotoxicity of chemotherapeutic drugs when combined with Doxorubicin or Gemcitabine. Our results indicate that XZH-5 may be a potential therapeutic agent for breast and pancreatic cancers with constitutive STAT3 signaling.
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23 MeSH Terms
Polymorphisms of the acid sensing histidine kinase gene arsS in Helicobacter pylori populations from anatomically distinct gastric sites.
Hallinger DR, Romero-Gallo J, Peek RM, Forsyth MH
(2012) Microb Pathog 53: 227-33
MeSH Terms: Aged, Alleles, Amplified Fragment Length Polymorphism Analysis, Cytidine, DNA, Bacterial, Female, Gastric Mucosa, Genotype, Helicobacter pylori, Histidine Kinase, Humans, Male, Middle Aged, Polymorphism, Genetic, Protein Kinases, Sequence Analysis, DNA, Sequence Deletion
Show Abstract · Added September 3, 2013
Phase variation is frequently utilized by bacterial species to affect gene expression such that phenotypic variants are maintained within populations, ensuring survival as environmental or host conditions change. Unusual among Helicobacter pylori phase variable or contingency genes is arsS, encoding a sensory histidine kinase involved in the acid acclimation of the organism. The presence of a 3' homopolymeric cytosine tract of variable length in arsS among Helicobacter pylori strains allows for the expression of various functional ArsS isoforms, differing in carboxy-terminal protein domains. In this study, we analyzed this 3'arsS region via amplified fragment length polymorphism (AFLP) and sequencing analyses for H. pylori populations from 3 different gastric sites of 12 patients. Our data indicate the presence of multiple arsS alleles within each population of H. pylori derived from the gastric antrum, cardia, or corpus of these patients. We also show that H. pylori, derived from the same anatomical site and patient, are predicted to express multiple ArsS isoforms in each population investigated. Furthermore, we identify a polymorphic deletion within arsS that generates another alternate ArsS C-terminal end. These findings suggest that four C-terminal variations of ArsS adds to the complexity of the ArsRS acid adaptation mechanism as a whole and may influence the ability of H. pylori to persist in the gastric niche for decades.
Copyright © 2012 Elsevier Ltd. All rights reserved.
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17 MeSH Terms
Nitric oxide modulates bacterial biofilm formation through a multicomponent cyclic-di-GMP signaling network.
Plate L, Marletta MA
(2012) Mol Cell 46: 449-60
MeSH Terms: 3',5'-Cyclic-GMP Phosphodiesterases, Amino Acid Sequence, Bacterial Proteins, Biofilms, Cyclic GMP, Gammaproteobacteria, Guanylate Cyclase, Histidine Kinase, Models, Biological, Molecular Sequence Data, Nitric Oxide, Phosphorylation, Protein Kinases, Protein Structure, Tertiary, Receptors, Cytoplasmic and Nuclear, Second Messenger Systems, Sequence Homology, Amino Acid, Shewanella, Signal Transduction, Soluble Guanylyl Cyclase
Show Abstract · Added March 3, 2020
Nitric oxide (NO) signaling in vertebrates is well characterized and involves the heme-nitric oxide/oxygen-binding (H-NOX) domain of soluble guanylate cyclase as a selective NO sensor. In contrast, little is known about the biological role or signaling output of bacterial H-NOX proteins. Here, we describe a molecular pathway for H-NOX signaling in Shewanella oneidensis. NO stimulates biofilm formation by controlling the levels of the bacterial secondary messenger cyclic diguanosine monophosphate (c-di-GMP). Phosphotransfer profiling was used to map the connectivity of a multicomponent signaling network that involves integration from two histidine kinases and branching to three response regulators. A feed-forward loop between response regulators with phosphodiesterase domains and phosphorylation-mediated activation intricately regulated c-di-GMP levels. Phenotypic characterization established a link between NO signaling and biofilm formation. Cellular adhesion may provide a protection mechanism for bacteria against reactive and damaging NO. These results are broadly applicable to H-NOX-mediated NO signaling in bacteria.
Copyright © 2012 Elsevier Inc. All rights reserved.
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Biomarker-mediated disruption of coffee-ring formation as a low resource diagnostic indicator.
Trantum JR, Wright DW, Haselton FR
(2012) Langmuir 28: 2187-93
MeSH Terms: Antigens, Protozoan, Biomarkers, Biomimetic Materials, Clinical Chemistry Tests, Fluorescent Dyes, Histidine, Limit of Detection, Magnets, Malaria, Microfluidic Analytical Techniques, Nanoparticles, Protozoan Proteins, Volatilization
Show Abstract · Added May 27, 2014
The ring pattern resulting from the unique microfluidics in an evaporating coffee drop is a well-studied mass transport phenomenon generating interest in the research community mostly from a mechanistic perspective. In this report, we describe how biomarker-induced particle-particle assemblies, magnetic separation, and evaporation-driven ring formation can be combined for simple pathogen detection. In this assay design, the presence of biomarkers causes self-assembly of a magnetic nanoparticle and a fluorescently labeled micrometer-sized particle. A small spherical magnet under the center of the drop prevents these assemblies from migrating to the drop's edge while a nonreactive control particle flows to the edge forming a ring pattern. Thus the presence or absence of biomarker results in distinctly different distributions of particles in the dried drop. Proof-of-principle studies using poly-L-histidine, a peptide mimic of the malaria biomarker pfHRPII, show that the predicted particle distributions occur with a limit of detection of approximately 200-300 nM.
© 2011 American Chemical Society
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13 MeSH Terms