6,076 results on '"Histidine kinase"'
Search Results
102. HAM-5 functions as a MAP kinase scaffold during cell fusion in Neurospora crassa.
- Author
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Jonkers, Wilfried, Leeder, Abigail C, Ansong, Charles, Wang, Yuexi, Yang, Feng, Starr, Trevor L, Camp, David G, Smith, Richard D, and Glass, N Louise
- Subjects
Neurospora crassa ,Spores ,Fungal ,Hyphae ,Protein Kinases ,Protein-Serine-Threonine Kinases ,MAP Kinase Kinase 2 ,Mitogen-Activated Protein Kinases ,Fungal Proteins ,Membrane Proteins ,Cell Fusion ,MAP Kinase Signaling System ,Histidine Kinase ,Developmental Biology ,Genetics - Abstract
Cell fusion in genetically identical Neurospora crassa germlings and in hyphae is a highly regulated process involving the activation of a conserved MAP kinase cascade that includes NRC-1, MEK-2 and MAK-2. During chemotrophic growth in germlings, the MAP kinase cascade members localize to conidial anastomosis tube (CAT) tips every ∼8 minutes, perfectly out of phase with another protein that is recruited to the tip: SOFT, a recently identified scaffold for the MAK-1 MAP kinase pathway in Sordaria macrospora. How the MAK-2 oscillation process is initiated, maintained and what proteins regulate the MAP kinase cascade is currently unclear. A global phosphoproteomics approach using an allele of mak-2 (mak-2Q100G) that can be specifically inhibited by the ATP analog 1NM-PP1 was utilized to identify MAK-2 kinase targets in germlings that were potentially involved in this process. One such putative target was HAM-5, a protein of unknown biochemical function. Previously, Δham-5 mutants were shown to be deficient for hyphal fusion. Here we show that HAM-5-GFP co-localized with NRC-1, MEK-2 and MAK-2 and oscillated with identical dynamics from the cytoplasm to CAT tips during chemotropic interactions. In the Δmak-2 strain, HAM-5-GFP localized to punctate complexes that did not oscillate, but still localized to the germling tip, suggesting that MAK-2 activity influences HAM-5 function/localization. However, MAK-2-GFP showed cytoplasmic and nuclear localization in a Δham-5 strain and did not localize to puncta. Via co-immunoprecipitation experiments, HAM-5 was shown to physically interact with NRC-1, MEK-2 and MAK-2, suggesting that it functions as a scaffold/transport hub for the MAP kinase cascade members for oscillation and chemotropic interactions during germling and hyphal fusion in N. crassa. The identification of HAM-5 as a scaffold-like protein will help to link the activation of MAK-2 cascade to upstream factors and proteins involved in this intriguing process of fungal communication.
- Published
- 2014
103. Mutual Exclusivity of Hyaluronan and Hyaluronidase in Invasive Group A Streptococcus *
- Author
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Henningham, Anna, Yamaguchi, Masaya, Aziz, Ramy K, Kuipers, Kirsten, Buffalo, Cosmo Z, Dahesh, Samira, Choudhury, Biswa, Van Vleet, Jeremy, Yamaguchi, Yuka, Seymour, Lisa M, Zakour, Nouri L Ben, He, Lingjun, Smith, Helen V, Grimwood, Keith, Beatson, Scott A, Ghosh, Partho, Walker, Mark J, Nizet, Victor, and Cole, Jason N
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Microbiology ,Biological Sciences ,Biomedical and Clinical Sciences ,Clinical Sciences ,Emerging Infectious Diseases ,Genetics ,Infectious Diseases ,2.2 Factors relating to the physical environment ,Aetiology ,Infection ,Animals ,Bacterial Proteins ,Base Sequence ,Cell Membrane ,Computational Biology ,Exotoxins ,Female ,Genetic Complementation Test ,Histidine Kinase ,Humans ,Hyaluronic Acid ,Hyaluronoglucosaminidase ,Intracellular Signaling Peptides and Proteins ,Mice ,Molecular Sequence Data ,Neutrophils ,Point Mutation ,Polysaccharide-Lyases ,Polysaccharides ,Recombinant Proteins ,Repressor Proteins ,Streptococcal Infections ,Streptococcus pyogenes ,Virulence ,Bacterial Pathogenesis ,Hyaluronan ,Hyaluronate ,Infectious Disease ,Streptococcus Pyogenes (S ,Pyogenes) ,Group A Streptococcus ,Hyaluronate Lyase ,Hyaluronic acid Capsule ,Invasive Disease ,Nonencapsulated ,Streptococcus Pyogenes ,Chemical Sciences ,Medical and Health Sciences ,Biochemistry & Molecular Biology ,Biological sciences ,Biomedical and clinical sciences ,Chemical sciences - Abstract
A recent analysis of group A Streptococcus (GAS) invasive infections in Australia has shown a predominance of M4 GAS, a serotype recently reported to lack the antiphagocytic hyaluronic acid (HA) capsule. Here, we use molecular genetics and bioinformatics techniques to characterize 17 clinical M4 isolates associated with invasive disease in children during this recent epidemiology. All M4 isolates lacked HA capsule, and whole genome sequence analysis of two isolates revealed the complete absence of the hasABC capsule biosynthesis operon. Conversely, M4 isolates possess a functional HA-degrading hyaluronate lyase (HylA) enzyme that is rendered nonfunctional in other GAS through a point mutation. Transformation with a plasmid expressing hasABC restored partial encapsulation in wild-type (WT) M4 GAS, and full encapsulation in an isogenic M4 mutant lacking HylA. However, partial encapsulation reduced binding to human complement regulatory protein C4BP, did not enhance survival in whole human blood, and did not increase virulence of WT M4 GAS in a mouse model of systemic infection. Bioinformatics analysis found no hasABC homologs in closely related species, suggesting that this operon was a recent acquisition. These data showcase a mutually exclusive interaction of HA capsule and active HylA among strains of this leading human pathogen.
- Published
- 2014
104. How Can a Histidine Kinase Respond to Mechanical Stress?
- Author
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Linda J. Kenney
- Subjects
mechanosignaling ,lipid allostery ,EnvZ ,histidine kinase ,nanodiscs ,catch bonds ,Microbiology ,QR1-502 - Abstract
Bacteria respond to physical forces perceived as mechanical stress as part of their comprehensive environmental sensing strategy. Histidine kinases can then funnel diverse environmental stimuli into changes in gene expression through a series of phosphorelay reactions. Because histidine kinases are most often embedded in the inner membrane, they can be sensitive to changes in membrane tension that occurs, for example, in response to osmotic stress, or when deformation of the cell body occurs upon encountering a surface before forming biofilms, or inside the host in response to shear stress in the kidney, intestine, lungs, or blood stream. A summary of our recent work that links the histidine kinase EnvZ to mechanical changes in the inner membrane is provided and placed in a context of other bacterial systems that respond to mechanical stress.
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- 2021
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105. How Can a Histidine Kinase Respond to Mechanical Stress?
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Kenney, Linda J.
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STRAINS & stresses (Mechanics) ,HISTIDINE ,SHEARING force ,HISTIDINE kinases ,GENE expression ,BIOFILMS - Abstract
Bacteria respond to physical forces perceived as mechanical stress as part of their comprehensive environmental sensing strategy. Histidine kinases can then funnel diverse environmental stimuli into changes in gene expression through a series of phosphorelay reactions. Because histidine kinases are most often embedded in the inner membrane, they can be sensitive to changes in membrane tension that occurs, for example, in response to osmotic stress, or when deformation of the cell body occurs upon encountering a surface before forming biofilms, or inside the host in response to shear stress in the kidney, intestine, lungs, or blood stream. A summary of our recent work that links the histidine kinase EnvZ to mechanical changes in the inner membrane is provided and placed in a context of other bacterial systems that respond to mechanical stress. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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106. Acetate and auto‐inducing peptide are independent triggers of quorum sensing in Lactobacillus plantarum.
- Author
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Meng, Fanqiang, Lu, Fengxia, Du, Hechao, Nie, Ting, Zhu, Xiaoyu, Connerton, Ian F., Zhao, Haizhen, Bie, Xiaomei, Zhang, Chong, Lu, Zhaoxin, and Lu, Yingjian
- Subjects
- *
QUORUM sensing , *LACTOBACILLUS plantarum , *FOOD fermentation , *HYDROGEN bonding interactions , *ACETATES , *HYDROPHOBIC interactions - Abstract
The synthesis of plantaricin in Lactobacillusplantarum is regulated by quorum sensing. However, the nature of the extra‐cytoplasmic (EC) sensing domain of the histidine kinase (PlnB1) and the ability to recognize the auto‐inducing peptide PlnA1 is not known. We demonstrate the key motif Ile‐Ser‐Met‐Leu of auto‐inducing peptide PlnA1 binds to the hydrophobic region Phe‐Ala‐Ser‐Gln‐Phe of EC loop 2 of PlnB1 via hydrophobic interactions and hydrogen bonding. Moreover, we identify a new inducer, acetate, that regulates the synthesis of plantaricin by binding to a positively charged region (Arg‐Arg‐Tyr‐Ser‐His‐Lys) in loop 4 of PlnB1 via electrostatic interaction. The side chain of Phe143 on loop 4 determined the specificity and affinity of PlnB1 to recognize acetate. PlnA1 activates quorum sensing in log phase growth and acetate in stationary phase to maintain the synthesis of plantaricin under conditions of reduced growth. Acetate activation of PlnB was also evident in four types of PlnB present in different Lb. plantarum strains. Finally, we proposed a model to explain the developmental regulation of plantaricin synthesis by PlnA and acetate. These results have potential applications in improving food fermentation and bacteriocin production. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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107. A high‐efficient strategy for combinatorial engineering paralogous gene family: A case study on histidine kinases in Clostridium.
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Zhu, Chao, Du, Guangqing, Zhang, Jie, and Xue, Chuang
- Abstract
Microorganisms harbor bulks of functionally similar or undefined genes, which belong to paralogous gene family. There is a necessity of exploring combinatorial or interactive functions of these genes, but conventional loss‐of‐function strategy with one‐by‐one rounds suffers extremely low efficiency for generating mutant libraries with all gene permutations. Here, taking histidine kinases (HKs) in Clostridium acetobutylicum as a proof‐of‐concept, we developed a multi‐plasmid cotransformation strategy for generating all theoretical HKs combinations in one round. For five HKs with 31 theoretical combinations, the library containing 22 mutants within all the possible HKs‐inactivated combinations was constructed with 11 days compared to 242 days by conventional strategy, while the other 9 combinations cannot survive. Six mutants with the enhanced butanol production and tolerance were obtained with changes of cell development during fermentation, one of which could produce 54.2% more butanol (56.4% more solvents), while the butanol production of other mutants was unchanged or decreased. The cotransformation strategy demonstrated potentials for fast exploring pleiotropic function of paralogous family genes in cell survival, cell development, and target product metabolism. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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108. Development of a reversible regulatory system for gene expression in the cyanobacterium Synechocystis sp. PCC 6803 by quorum-sensing machinery from marine bacteria.
- Author
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Junaid, Muhammad, Inaba, Yu, Otero, Ana, and Suzuki, Iwane
- Abstract
Histidine kinases are common sensory proteins used to detect environmental changes in bacteria. They respond to specific stimuli via a signal-input domain and alter gene expression through a cognate response regulator. The modulation/control of transcriptional regulation in cyanobacteria is important to reinforce the production of useful target compounds via photosynthesis without altering the growth profiles. For instance, heavy metal ions (Ni2+ and Cu2+), chemical inducers (IPTG), and a volatile compound (toluene) have been previously applied to regulate gene expression in cyanobacteria. However, most systems/regulators are only able to regulate gene expression once because it is impossible to eliminate them from the medium. To construct a reversible regulation system, a chimeric sensor, VanN_SphS, was developed by fusing the signal input domain of a quorum-sensing (QS) sensor, VanN, from Vibrio anguillarum, responding N-3-hydroxyhexanoyl-L-homoserine lactone (OHC6-HSL), with the kinase domain of SphS, a phosphate-deficiency sensor from the cyanobacterium Synechocystis sp. PCC 6803. After expression of the chimeric sensor in Synechocystis cells, responses to the various N-acyl-homoserine-lactones (AHLs) were evaluated by measuring the alkaline phosphatase (AP) activity, which is regulated by SphS. VanN_SphS responded only to OHC6-HSL and repressed AP activity. Then, the coexpression of the AHLs-degradation enzyme, Aii20J, a lactonase from Tenacibaculum sp. 20J, resumed the activity. This is the first report on the use of AHL-mediated transcriptional regulation in Synechocystis, which could be used in the future for the controlled production of useful compounds in the cyanobacterium. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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109. Two-Component Signaling Systems Regulate Diverse Virulence-Associated Traits in Pseudomonas aeruginosa.
- Author
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Wang, Benjamin X., Cady, Kyle C., Oyarce, Gerardo C., Ribbeck, Katharina, and Laub, Michael T.
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HISTIDINE kinases , *PSEUDOMONAS aeruginosa , *PHENOTYPES , *HUMAN body , *CELLULAR signal transduction - Abstract
Pseudomonas aeruginosa is an opportunistic pathogen that can cause problematic infections at different sites throughout the human body. P. aeruginosa encodes a large suite of over 60 two-component signaling systems that enable cells to rapidly sense and respond to external signals. Previous work has shown that some of these sensory systems contribute to P. aeruginosa pathogenesis, but the virulence-associated processes and phenotypic traits that each of these systems controls are still largely unclear. To aid investigations of these sensory systems, we have generated deletion strains for each of 64 genes encoding histidine kinases and one histidine phosphotransferase in P. aeruginosa PA14. We carried out initial phenotypic characterizations of this collection by assaying these mutants for over a dozen virulence-associated traits, and we found that each of these phenotypes is regulated by multiple sensory systems. Our work highlights the usefulness of this collection for further studies of P. aeruginosa two-component signaling systems and provides insight into how these systems may contribute to P. aeruginosa infection. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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110. The Molecular Mechanism of Fludioxonil Action Is Different to Osmotic Stress Sensing .
- Author
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Bersching, Katharina and Jacob, Stefan
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- *
FLUDIOXONIL , *HISTIDINE , *PYRICULARIA oryzae , *OSMOLAR concentration , *SORBITOL - Abstract
The group III two-component hybrid histidine kinase MoHik1p in the filamentous fungus Magnaporthe oryzae is known to be a sensor for external osmotic stress and essential for the fungicidal activity of the phenylpyrrole fludioxonil. The mode of action of fludioxonil has not yet been completely clarified but rather assumed to hyperactivate the high osmolarity glycerol (HOG) signaling pathway. To date, not much is known about the detailed molecular mechanism of how osmotic stress is detected or fungicidal activity is initiated within the HOG pathway. The molecular mechanism of signaling was studied using a mutant strain in which the HisKA signaling domain was modified by an amino acid change of histidine H736 to alanine A736. We found that MoHik1pH736A is as resistant to fludioxonil but not as sensitive to osmotic stress as the null mutant ∆Mohik1. H736 is required for fludioxonil action but is not essential for sensing sorbitol stress. Consequently, this report provides evidence of the difference in the molecular mechanism of fludioxonil action and the perception of osmotic stress. This is an excellent basis to understand the successful phenylpyrrole-fungicides’ mode of action better and will give new ideas to decipher cellular signaling mechanisms. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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111. Perception and protection: The role of Bce-modules in antimicrobial peptide resistance.
- Author
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Orlando, Benjamin J.
- Subjects
- *
ANTIMICROBIAL peptides , *DRUG resistance in microorganisms , *MEMBRANE proteins , *BACILLUS subtilis , *GRAM-positive bacteria , *ATP-binding cassette transporters , *CATHELICIDINS , *PEPTIDE antibiotics - Abstract
Continual synthesis and remodeling of the peptidoglycan layer surrounding Gram-positive cells is essential for their survival. Diverse antimicrobial peptides target the lipid intermediates involved in this process. To sense and counteract assault from antimicrobial peptides, low G + C content gram-positive bacteria (Firmicutes) have evolved membrane protein complexes known as Bce-modules. These complexes consist minimally of an ABC transporter and a two-component system that work in tandem to perceive and confer resistance against antimicrobial peptides. In this mini-review I highlight recent breakthroughs in comprehending the structure and function of these unusual membrane protein complexes, with a particular focus on the BceAB-RS system present in Bacillus subtilis. [Display omitted] • Antimicrobial peptides bind to intermediates of the lipid II cycle. • Bce transporters provide resistance against antimicrobial peptides. • Bce-modules are a membrane protein complex of ABC transporter and histidine kinase. • Bce-modules utilize flux-sensing and target-protection mechanisms. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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112. Cys-Scanning Disulfide Crosslinking and Bayesian Modeling Probe the Transmembrane Signaling Mechanism of the Histidine Kinase, PhoQ
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Molnar, Kathleen S, Bonomi, Massimiliano, Pellarin, Riccardo, Clinthorne, Graham D, Gonzalez, Gabriel, Goldberg, Shalom D, Goulian, Mark, Sali, Andrej, and DeGrado, William F
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Biochemistry and Cell Biology ,Biological Sciences ,Bacterial Proteins ,Bayes Theorem ,Computer Simulation ,Cystine ,Histidine Kinase ,Models ,Molecular ,Protein Kinases ,Protein Structure ,Secondary ,Protein Structure ,Tertiary ,Structural Homology ,Protein ,Chemical Sciences ,Information and Computing Sciences ,Biophysics ,Biological sciences ,Chemical sciences - Abstract
Bacteria transduce signals across the membrane using two-component systems (TCSs), consisting of a membrane-spanning sensor histidine kinase and a cytoplasmic response regulator. In gram-negative bacteria, the PhoPQ TCS senses cations and antimicrobial peptides, yet little is known about the structural changes involved in transmembrane signaling. We construct a model of PhoQ signal transduction using Bayesian inference, based on disulfide crosslinking data and homologous crystal structures. The data are incompatible with a single conformation but are instead consistent with two interconverting structures. These states differ in membrane depth of the periplasmic acidic patch and the reciprocal displacement of diagonal helices along the dimer interface. Studies of multiple histidine kinases suggest this repacking might be a common mode of signal transduction in sensor His-kinase receptors. Because a similar scissors model has been ruled out in CheA-linked chemoreceptors, the evidence suggests that sensor His-kinase and CheA-linked receptors possess different signaling mechanisms.
- Published
- 2014
113. The Linker between the Dimerization and Catalytic Domains of the CheA Histidine Kinase Propagates Changes in Structure and Dynamics That Are Important for Enzymatic Activity
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Wang, Xiqing, Vallurupalli, Pramodh, Vu, Anh, Lee, Kwangwoon, Sun, Sheng, Bai, Wen-Ju, Wu, Chun, Zhou, Hongjun, Shea, Joan-Emma, Kay, Lewis E, and Dahlquist, Frederick W
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Biochemistry and Cell Biology ,Chemical Sciences ,Biological Sciences ,Bacterial Proteins ,Catalytic Domain ,Enzyme Activation ,Histidine Kinase ,Models ,Molecular ,Phosphorylation ,Protein Kinases ,Protein Multimerization ,Thermotoga maritima ,Medicinal and Biomolecular Chemistry ,Medical Biochemistry and Metabolomics ,Biochemistry & Molecular Biology ,Biochemistry and cell biology ,Medical biochemistry and metabolomics ,Medicinal and biomolecular chemistry - Abstract
The histidine kinase, CheA, couples environmental stimuli to changes in bacterial swimming behavior, converting a sensory signal to a chemical signal in the cytosol via autophosphorylation. The kinase activity is regulated in the platform of chemotaxis signaling complexes formed by CheW, chemoreceptors, and the regulatory domain of CheA. Our previous computational and mutational studies have revealed that two interdomain linkers play important roles in CheA's enzymatic activity. Of the two linkers, one that connects the dimerization and ATP binding domains is essential for both basal autophosphorylation and activation of the kinase. However, the mechanistic role of this linker remains unclear, given that it is far from the autophosphorylation reaction center (the ATP binding site). Here we investigate how this interdomain linker is coupled to CheA's enzymatic activity. Using modern nuclear magnetic resonance (NMR) techniques, we find that by interacting with the catalytic domain, the interdomain linker initiates long-range structural and dynamic changes directed toward the catalytic center of the autophosphorylation reaction. Subsequent biochemical assays define the functional relevance of these NMR-based observations. These findings extend our understanding of the chemotaxis signal transduction pathway.
- Published
- 2014
114. Diversification of cytokinin phosphotransfer signaling genes in Medicago truncatula and other legume genomes
- Author
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Sovanna Tan, Frédéric Debellé, Pascal Gamas, Florian Frugier, and Mathias Brault
- Subjects
Phosphorelay ,Cytokinin signaling ,Histidine kinase ,Response regulator ,Legumes ,Symbiotic nitrogen-fixing nodulation ,Biotechnology ,TP248.13-248.65 ,Genetics ,QH426-470 - Abstract
Abstract Background Legumes can establish on nitrogen-deprived soils a symbiotic interaction with Rhizobia bacteria, leading to the formation of nitrogen-fixing root nodules. Cytokinin phytohormones are critical for triggering root cortical cell divisions at the onset of nodule initiation. Cytokinin signaling is based on a Two-Component System (TCS) phosphorelay cascade, involving successively Cytokinin-binding Histidine Kinase receptors, phosphorelay proteins shuttling between the cytoplasm and the nucleus, and Type-B Response Regulator (RRB) transcription factors activating the expression of cytokinin primary response genes. Among those, Type-A Response Regulators (RRA) exert a negative feedback on the TCS signaling. To determine whether the legume plant nodulation capacity is linked to specific features of TCS proteins, a genome-wide identification was performed in six legume genomes (Cajanus cajan, pigeonpea; Cicer arietinum, chickpea; Glycine max, soybean; Phaseolus vulgaris, common bean; Lotus japonicus; Medicago truncatula). The diversity of legume TCS proteins was compared to the one found in two non-nodulating species, Arabidopsis thaliana and Vitis vinifera, which are references for functional analyses of TCS components and phylogenetic analyses, respectively. Results A striking expansion of non-canonical RRBs was identified, notably leading to the emergence of proteins where the conserved phosphor-accepting aspartate residue is replaced by a glutamate or an asparagine. M. truncatula genome-wide expression datasets additionally revealed that only a limited subset of cytokinin-related TCS genes is highly expressed in different organs, namely MtCHK1/MtCRE1, MtHPT1, and MtRRB3, suggesting that this “core” module potentially acts in most plant organs including nodules. Conclusions Further functional analyses are required to determine the relevance of these numerous non-canonical TCS RRBs in symbiotic nodulation, as well as of canonical MtHPT1 and MtRRB3 core signaling elements.
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- 2019
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115. Phytochromes in Agrobacterium fabrum
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Tilman Lamparter, Peng Xue, Afaf Elkurdi, Gero Kaeser, Luisa Sauthof, Patrick Scheerer, and Norbert Krauß
- Subjects
crystal structure ,protein conformational changes ,plant infection ,bacterial conjugation ,light regulation ,histidine kinase ,Plant culture ,SB1-1110 - Abstract
The focus of this review is on the phytochromes Agp1 and Agp2 of Agrobacterium fabrum. These are involved in regulation of conjugation, gene transfer into plants, and other effects. Since crystal structures of both phytochromes are known, the phytochrome system of A. fabrum provides a tool for following the entire signal transduction cascade starting from light induced conformational changes to protein interaction and the triggering of DNA transfer processes.
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- 2021
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116. Spatiotemporal Models of the Asymmetric Division Cycle of Caulobacter crescentus
- Author
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Subramanian, Kartik, Tyson, John J., Kubiak, Jacek Z., Series editor, Kloc, Malgorzata, Series editor, and Tassan, Jean-Pierre, editor
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- 2017
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117. Signaling Mechanisms in Pathogenesis and Virulence of Candida albicans
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Chauhan, Neeraj and Prasad, Rajendra, editor
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- 2017
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118. Phytochromes in Agrobacterium fabrum.
- Author
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Lamparter, Tilman, Xue, Peng, Elkurdi, Afaf, Kaeser, Gero, Sauthof, Luisa, Scheerer, Patrick, and Krauß, Norbert
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PHYTOCHROMES ,AGROBACTERIUM ,GENETIC transformation ,PROTEIN-protein interactions ,PLANT genes - Abstract
The focus of this review is on the phytochromes Agp1 and Agp2 of Agrobacterium fabrum. These are involved in regulation of conjugation, gene transfer into plants, and other effects. Since crystal structures of both phytochromes are known, the phytochrome system of A. fabrum provides a tool for following the entire signal transduction cascade starting from light induced conformational changes to protein interaction and the triggering of DNA transfer processes. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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119. Novel Two-Component System-Like Elements Reveal Functional Domains Associated with Restriction–Modification Systems and paraMORC ATPases in Bacteria.
- Author
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Bellieny-Rabelo, Daniel, Pretorius, Willem J S, and Moleleki, Lucy N
- Subjects
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DNA modification & restriction , *GENES , *PROTEIN domains , *METHYLTRANSFERASES , *BACTERIA - Abstract
Two-component systems (TCS) are important types of machinery allowing for efficient signal recognition and transmission in bacterial cells. The majority of TCSs utilized by bacteria is composed of a sensor histidine kinase (HK) and a cognate response regulator (RR). In the present study, we report two newly predicted protein domains—both to be included in the next release of the Pfam database: Response_reg_2 (PF19192) and HEF_HK (PF19191)—in bacteria which exhibit high structural similarity, respectively, with typical domains of RRs and HKs. Additionally, the genes encoding for the novel predicted domains exhibit a 91.6% linkage observed across 644 genomic regions recovered from 628 different bacterial strains. The remarkable adjacent colocalization between genes carrying Response_reg_2 and HEF_HK in addition to their conserved structural features, which are highly similar to those from well-known HKs and RRs, raises the possibility of Response_reg_2 and HEF_HK constituting a new TCS in bacteria. The genomic regions in which these predicted two-component systems-like are located additionally exhibit an overrepresented presence of restriction–modification (R–M) systems especially the type II R–M. Among these, there is a conspicuous presence of C-5 cytosine-specific DNA methylases which may indicate a functional association with the newly discovered domains. The solid presence of R–M systems and the presence of the GHKL family domain HATPase_c_3 across most of the HEF_HK-containing genes are also indicative that these genes are evolutionarily related to the paraMORC family of ATPases. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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120. Tightening the Screws on PsbA in Cyanobacteria.
- Author
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Srivastava, Amit and Shukla, Pratyoosh
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- *
PHOTOSYSTEMS , *CYANOBACTERIA , *SCREWS , *CELLULAR signal transduction , *GENE expression - Abstract
Cyanobacterial genomes encode several isoforms of the D1 (PsbA) subunit of Photosystem II (PSII). The distinct regulation of each isoform ensures adaptation under changing environmental conditions. Uncovering the missing elements of signal transduction pathways and psbA gene expression could open new avenues in engineering programs of cyanobacterial strains. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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121. Assembly of the transmembrane domain of E. coli PhoQ histidine kinase: implications for signal transduction from molecular simulations.
- Author
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Lemmin, Thomas, Soto, Cinque, Clinthorne, Graham, Dal Peraro, Matteo, and Degrado, William
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Escherichia coli ,Histidine Kinase ,Membrane Proteins ,Models ,Molecular ,Molecular Dynamics Simulation ,Protein Kinases ,Signal Transduction - Abstract
The PhoQP two-component system is a signaling complex essential for bacterial virulence and cationic antimicrobial peptide resistance. PhoQ is the histidine kinase chemoreceptor of this tandem machine and assembles in a homodimer conformation spanning the bacterial inner membrane. Currently, a full understanding of the PhoQ signal transduction is hindered by the lack of a complete atomistic structure. In this study, an atomistic model of the key transmembrane (TM) domain is assembled by using molecular simulations, guided by experimental cross-linking data. The formation of a polar pocket involving Asn202 in the lumen of the tetrameric TM bundle is crucial for the assembly and solvation of the domain. Moreover, a concerted displacement of the TM helices at the periplasmic side is found to modulate a rotation at the cytoplasmic end, supporting the transduction of the chemical signal through a combination of scissoring and rotational movement of the TM helices.
- Published
- 2013
122. Impacts of fludioxonil resistance on global gene expression in the necrotrophic fungal plant pathogen Sclerotinia sclerotiorum.
- Author
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Taiwo, Akeem O., Harper, Lincoln A., and Derbyshire, Mark C.
- Subjects
- *
SCLEROTINIA sclerotiorum , *GENE expression , *PHYTOPATHOGENIC microorganisms , *OSMOTIC pressure , *GENES , *NEUROSPORA crassa , *GENE regulatory networks - Abstract
Background: The fungicide fludioxonil over-stimulates the fungal response to osmotic stress, leading to over-accumulation of glycerol and hyphal swelling and bursting. Fludioxonil-resistant fungal strains that are null-mutants for osmotic stress response genes are easily generated through continual sub-culturing on sub-lethal fungicide doses. Using this approach combined with RNA sequencing, we aimed to characterise the effects of mutations in osmotic stress response genes on the transcriptional profile of the important agricultural pathogen Sclerotinia sclerotiorum under standard laboratory conditions. Our objective was to understand the impact of disruption of the osmotic stress response on the global transcriptional regulatory network in an important agricultural pathogen. Results: We generated two fludioxonil-resistant S. sclerotiorum strains, which exhibited growth defects and hypersensitivity to osmotic stressors. Both had missense mutations in the homologue of the Neurospora crassa osmosensing two component histidine kinase gene OS1, and one had a disruptive in-frame deletion in a non-associated gene. RNA sequencing showed that both strains together differentially expressed 269 genes relative to the parent during growth in liquid broth. Of these, 185 (69%) were differentially expressed in both strains in the same direction, indicating similar effects of the different point mutations in OS1 on the transcriptome. Among these genes were numerous transmembrane transporters and secondary metabolite biosynthetic genes. Conclusions: Our study is an initial investigation into the kinds of processes regulated through the osmotic stress pathway in S. sclerotiorum. It highlights a possible link between secondary metabolism and osmotic stress signalling, which could be followed up in future studies. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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123. ‘84K’ 杨组氨酸激酶基因 PaHK3b 的 克隆及功能分析.
- Author
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鲁俊倩, 武 舒, 钟姗辰, 张伟溪, 苏晓华, and 张冰玉
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PLANT hormones ,GENES ,PROMOTERS (Genetics) ,SALICYLIC acid ,ABIOTIC stress ,AMINO acids ,CYTOKININS ,MOLECULAR cloning - Abstract
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- Published
- 2021
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124. Engineering a fumaric acid-responsive two-component biosensor for dynamic range improvement in Escherichia coli
- Author
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Yang, Huiqin, Yang, Xiaoyan, Lu, Yanbo, Shu, Quanxian, Zhou, Shenghu, and Deng, Yu
- Published
- 2022
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125. What do archaeal and eukaryotic histidine kinases sense? [version 1; peer review: 3 approved]
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Nicolas Papon and Ann M. Stock
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Review ,Articles ,two-component system ,histidine kinase ,sensor ,evolution ,signal transduction ,phosphorylation - Abstract
Signal transduction systems configured around a core phosphotransfer step between a histidine kinase and a cognate response regulator protein occur in organisms from all domains of life. These systems, termed two-component systems, constitute the majority of multi-component signaling pathways in Bacteria but are less prevalent in Archaea and Eukarya. The core signaling domains are modular, allowing versatility in configuration of components into single-step phosphotransfer and multi-step phosphorelay pathways, the former being predominant in bacteria and the latter in eukaryotes. Two-component systems regulate key cellular regulatory processes that provide adaptive responses to environmental stimuli and are of interest for the development of antimicrobial therapeutics, biotechnology applications, and biosensor engineering. In bacteria, two-component systems have been found to mediate responses to an extremely broad array of extracellular and intracellular chemical and physical stimuli, whereas in archaea and eukaryotes, the use of two-component systems is more limited. This review summarizes recent advances in exploring the repertoire of sensor histidine kinases in the Archaea and Eukarya domains of life.
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- 2019
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126. Crosstalk involving two-component systems in Staphylococcus aureus signaling networks.
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Ali L and Abdel Aziz MH
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- Humans, Signal Transduction physiology, Histidine Kinase, Bacteria, Staphylococcus aureus genetics, Bacterial Proteins genetics
- Abstract
Staphylococcus aureus poses a serious global threat to human health due to its pathogenic nature, adaptation to environmental stress, high virulence, and the prevalence of antimicrobial resistance. The signaling network in S. aureus coordinates and integrates various internal and external inputs and stimuli to adapt and formulate a response to the environment. Two-component systems (TCSs) of S. aureus play a central role in this network where surface-expressed histidine kinases (HKs) receive and relay external signals to their cognate response regulators (RRs). Despite the purported high fidelity of signaling, crosstalk within TCSs, between HK and non-cognate RR, and between TCSs and other systems has been detected widely in bacteria. The examples of crosstalk in S. aureus are very limited, and there needs to be more understanding of its molecular recognition mechanisms, although some crosstalk can be inferred from similar bacterial systems that share structural similarities. Understanding the cellular processes mediated by this crosstalk and how it alters signaling, especially under stress conditions, may help decipher the emergence of antibiotic resistance. This review highlights examples of signaling crosstalk in bacteria in general and S. aureus in particular, as well as the effect of TCS mutations on signaling and crosstalk., Competing Interests: The authors declare no conflict of interest.
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- 2024
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127. Binding Mode and Molecular Mechanism of the Two-Component Histidine Kinase Bos1 of Botrytis cinerea to Fludioxonil and Iprodione.
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Yin X, Li P, Wang Z, Wang J, Fang A, Tian B, Yang Y, Yu Y, and Bi C
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- Plant Diseases microbiology, Molecular Docking Simulation, Mutation, Mutagenesis, Site-Directed, Botrytis genetics, Botrytis drug effects, Botrytis enzymology, Dioxoles pharmacology, Fungicides, Industrial pharmacology, Drug Resistance, Fungal genetics, Fungal Proteins genetics, Fungal Proteins metabolism, Hydantoins pharmacology, Pyrroles pharmacology, Pyrroles metabolism, Histidine Kinase genetics, Histidine Kinase metabolism, Aminoimidazole Carboxamide analogs & derivatives
- Abstract
Gray mold caused by Botrytis cinerea is among the 10 most serious fungal diseases worldwide. Fludioxonil is widely used to prevent and control gray mold due to its low toxicity and high efficiency; however, resistance caused by long-term use has become increasingly prominent. Therefore, exploring the resistance mechanism of fungicides provides a theoretical basis for delaying the occurrence of diseases and controlling gray mold. In this study, fludioxonil-resistant strains were obtained through indoor drug domestication, and the mutation sites were determined by sequencing. Strains obtained by site-directed mutagenesis were subjected to biological analysis, and the binding modes of fludioxonil and iprodione to Botrytis cinerea Bos1 BcBos1 were predicted by molecular docking. The results showed that F127S, I365S/N, F127S + I365N, and I376M mutations on the Bos1 protein led to a decrease in the binding energy between the drug and BcBos1 . The A1259T mutation did not lead to a decrease in the binding energy, which was not the cause of drug resistance. The biological fitness of the fludioxonil- and point mutation-resistant strains decreased, and their growth rate, sporulation rate, and pathogenicity decreased significantly. The glycerol content of the sensitive strains was significantly lower than that of the resistant strains and increased significantly after treatment with 0.1 μg/ml of fludioxonil, whereas that of the resistant strains decreased. The osmotic sensitivity of the resistant strains was significantly lower than that of the sensitive strains. Positive cross-resistance was observed between fludioxonil and iprodione. These results will help to understand the resistance mechanism of fludioxonil in Botrytis cinerea more deeply., Competing Interests: The author(s) declare no conflict of interest.
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- 2024
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128. Darkness inhibits autokinase activity of bacterial bathy phytochromes.
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Huber C, Strack M, Schultheiß I, Pielage J, Mechler X, Hornbogen J, Diller R, and Frankenberg-Dinkel N
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- Histidine Kinase metabolism, Histidine Kinase genetics, Light, Photoreceptors, Microbial metabolism, Pseudomonas aeruginosa enzymology, Pseudomonas aeruginosa metabolism, Enzyme Activation, Bacterial Proteins metabolism, Bacterial Proteins genetics, Darkness, Phytochrome metabolism, Phytochrome chemistry
- Abstract
Bathy phytochromes are a subclass of bacterial biliprotein photoreceptors that carry a biliverdin IXα chromophore. In contrast to prototypical phytochromes that adopt a red-light-absorbing Pr ground state, the far-red light-absorbing Pfr-form is the thermally stable ground state of bathy phytochromes. Although the photobiology of bacterial phytochromes has been extensively studied since their discovery in the late 1990s, our understanding of the signal transduction process to the connected transmitter domains, which are often histidine kinases, remains insufficient. Initiated by the analysis of the bathy phytochrome PaBphP from Pseudomonas aeruginosa, we performed a systematic analysis of five different bathy phytochromes with the aim to derive a general statement on the correlation of photostate and autokinase output. While all proteins adopt different Pr/Pfr-fractions in response to red, blue, and far-red light, only darkness leads to a pure or highly enriched Pfr-form, directly correlated with the lowest level of autokinase activity. Using this information, we developed a method to quantitatively correlate the autokinase activity of phytochrome samples with well-defined stationary Pr/Pfr-fractions. We demonstrate that the off-state of the phytochromes is the Pfr-form and that different Pr/Pfr-fractions enable the organisms to fine-tune their kinase output in response to a certain light environment. Furthermore, the output response is regulated by the rate of dark reversion, which differs significantly from 5 s to 50 min half-life. Overall, our study indicates that bathy phytochromes function as sensors of light and darkness, rather than red and far-red light, as originally postulated., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2024
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129. Conserved patterns of sequence diversification provide insight into the evolution of two-component systems in Enterobacteriaceae .
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Barretto LAF, Van PT, and Fowler CC
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- Alleles, Amino Acid Sequence, Klebsiella
- Abstract
Two-component regulatory systems (TCSs) are a major mechanism used by bacteria to sense and respond to their environments. Many of the same TCSs are used by biologically diverse organisms with different regulatory needs, suggesting that the functions of TCS must evolve. To explore this topic, we analysed the amino acid sequence divergence patterns of a large set of broadly conserved TCS across different branches of Enterobacteriaceae , a family of Gram-negative bacteria that includes biomedically important genera such as Salmonella , Escherichia , Klebsiella and others. Our analysis revealed trends in how TCS sequences change across different proteins or functional domains of the TCS, and across different lineages. Based on these trends, we identified individual TCS that exhibit atypical evolutionary patterns. We observed that the relative extent to which the sequence of a given TCS varies across different lineages is generally well conserved, unveiling a hierarchy of TCS sequence conservation with EnvZ/OmpR as the most conserved TCS. We provide evidence that, for the most divergent of the TCS analysed, PmrA/PmrB, different alleles were horizontally acquired by different branches of this family, and that different PmrA/PmrB sequence variants have highly divergent signal-sensing domains. Collectively, this study sheds light on how TCS evolve, and serves as a compendium for how the sequences of the TCS in this family have diverged over the course of evolution.
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- 2024
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130. Characterization of SsHog1 and Shk1 Using Efficient Gene Knockout Systems through Repeated Protoplasting and CRISPR/Cas9 Ribonucleoprotein Approaches in Sclerotinia sclerotiorum .
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Ma J, Park SW, Kim G, Kim CS, Chang HX, Chilvers MI, and Sang H
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- Gene Knockout Techniques, Histidine Kinase genetics, CRISPR-Cas Systems, Ascomycota metabolism
- Abstract
Sclerotinia sclerotiorum is the causal agent of sclerotinia stem rot in over 400 plant species. In a previous study, the group III histidine kinase gene of S. sclerotiorum ( Shk1 ) revealed its involvement in iprodione and fludioxonil sensitivity and osmotic stress. To further investigate the fungicide sensitivity associated with the high-osmolarity glycerol (HOG) pathway, we functionally characterized SsHog1 , which is the downstream kinase of Shk1 . To generate knockout mutants, split marker transformation combined with a newly developed repeated protoplasting method and CRISPR/Cas9 ribonucleoprotein (RNP) delivery approach were used. The pure SsHog1 and Shk1 knockout mutants showed reduced sensitivity to fungicides and increased sensitivity to osmotic stress. In addition, the SsHog1 knockout mutants demonstrated reduced virulence compared to Shk1 knockout mutants and wild-type. Our results indicate that the repeated protoplasting method and RNP approach can generate genetically pure homokaryotic mutants and SsHog1 is involved in osmotic adaptation, fungicide sensitivity, and virulence in S. sclerotiorum .
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- 2024
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131. Identification of Uncharacterized Components of Prokaryotic Immune Systems and Their Diverse Eukaryotic Reformulations.
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Burroughs, A. Maxwell and Aravind, L.
- Abstract
Nucleotide-activated effector deployment, prototyped by interferondependent immunity, is a common mechanistic theme shared by immune systems of several animals and prokaryotes. Prokaryotic versions include CRISPR-Cas with the CRISPR polymerase domain, their minimal variants, and systems with second messenger oligonucleotide or dinucleotide synthetase (SMODS). Cyclic or linear oligonucleotide signals in these systems help set a threshold for the activation of potentially deleterious downstream effectors in response to invader detection. We establish such a regulatory mechanism to be a more general principle of immune systems, which can also operate independently of such messengers. Using sensitive sequence analysis and comparative genomics, we identify 12 new prokaryotic immune systems, which we unify by this principle of threshold-dependent effector activation. These display regulatory mechanisms paralleling physiological signaling based on 3=-5= cyclic mononucleotides, NAD+-derived messengers, two- and one-component signaling that includes histidine kinase-based signaling, and proteolytic activation. Furthermore, these systems allowed the identification of multiple new sensory signal sensory components, such as a tetratricopeptide repeat (TPR) scaffold predicted to recognize NAD+-derived signals, unreported versions of the STING domain, prokaryotic YEATS domains, and a predicted nucleotide sensor related to receiver domains. We also identify previously unrecognized invader detection components and effector components, such as prokaryotic versions of the Wnt domain. Finally, we show that there have been multiple acquisitions of unidentified STING domains in eukaryotes, while the TPR scaffold was incorporated into the animal immunity/apoptosis signalregulating kinase (ASK) signalosome. IMPORTANCE Both prokaryotic and eukaryotic immune systems face the dangers of premature activation of effectors and degradation of self-molecules in the absence of an invader. To mitigate this, they have evolved threshold-setting regulatory mechanisms for the triggering of effectors only upon the detection of a sufficiently strong invader signal. This work defines general templates for such regulation in effectorbased immune systems. Using this, we identify several previously uncharacterized prokaryotic immune mechanisms that accomplish the regulation of downstream effector deployment by using nucleotide, NAD+-derived, two-component, and onecomponent signals paralleling physiological homeostasis. This study has also helped identify several previously unknown sensor and effector modules in these systems. Our findings also augment the growing evidence for the emergence of key animal immunity and chromatin regulatory components from prokaryotic progenitors. [ABSTRACT FROM AUTHOR]
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- 2020
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132. Structural analysis of the sensor domain of the β-lactam antibiotic receptor VbrK from Vibrio parahaemolyticus.
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Cho, So Yeon and Yoon, Sung-il
- Subjects
- *
BETA lactam antibiotics , *VIBRIO parahaemolyticus , *GRAM-negative bacteria , *ANTIBIOTICS , *PEPTIDOGLYCANS , *DETECTORS , *CRYSTAL structure , *BACTERIA - Abstract
Bacteria express β-lactamase to counteract the bactericidal effects of β-lactam antibiotics, which are the most widely employed antibacterial drugs. In gram-negative bacteria, the expression of β-lactamase is generally regulated in response to the muropeptide that is generated from the peptidoglycan of the cell wall during β-lactam antibiotic challenge. The direct regulation of β-lactamase expression by β-lactams was recently reported in Vibrio parahaemolyticus , and this regulation is mediated by a two-component regulatory system that consists of the histidine kinase VbrK and the response regulator VbrR. VbrK directly recognizes β-lactam antibiotics using the periplasmic sensor domain (VbrKSD), a PF11884 Pfam family member, and it delivers the β-lactam signal to VbrR to induce the transcription of the β-lactamase gene. To determine the structural features of VbrKSD as the prototype of the PF11884 family and provide insights into the β-lactam antibiotic-binding mode of VbrKSD, we determined the crystal structure of VbrKSD at 1.65 Å resolution. VbrKSD folds into a unique curved rod-like structure that has not been previously reported in other families. VbrKSD consists of two domains (D1 and D2). The D1 domain contains two helix-decorated β-sheets, and the D2 domain adopts a helix-rich structure. VbrKSD features two terminal disulfide bonds, which would be the canonical property of the PF11884 family. In the VbrKSD structure, the L82 residue, which was previously shown to play a key role in β-lactam antibiotic recognition, forms a pocket along with its neighboring hydrophobic or positively charged residues. • The monomeric structure of the sensor domain of VbrK (VbrKSD) was determined. • VbrKSD consists of two domains and is shaped into a unique curved rod-like structure. • The PF11884 family, which includes VbrKSD, is characterized by cysteine residues. • The VbrK L82 residue that was shown to be required for penicillin binding forms a pocket. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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133. Role of Signal Transduction Domains in Histidine Kinase Evolution and Activity
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Mensa, Bruk
- Subjects
Biology ,Molecular biology ,Biophysics ,Allostery ,HAMP ,Histidine Kinase ,Library ,modeling ,signal transduction - Abstract
The process by which various upstream sensor and signal-transduction domains of bacterial histidine kinases (HKs) modulate the activity of the conserved autokinase domain remains poorly understood. Specifically, why do most HKs contain modularly inserted signal transduction domains? How do HKs robustly evolve and finetune the coupling between stimulus sensor domains and the conserved autokinase domain, which are often separated by 10s of nanometers? What is the role of these intervening domains in fine-tuning signaling parameters such as the minimum/maximum responsiveness, mid-point, and steepness of signal transition of an HK? In this work, we examine signal transduction through model E. coli HKs, PhoQ and CpxA, which contain one of the most abundant signal transduction domains in HKs, the HAMP domain. We first generate a large set of single-point mutants of PhoQ, and simultaneously measure the signaling state of the ligand-binding sensor and the kinase activity of the autokinase in vitro, at several inducing ligand concentrations to assess the coupling between these two domains. We demonstrate that point mutants in the HAMP signal transduction domain significantly modulate the coupled behavior of the sensor and autokinase, producing markedly varied ligand-dependent responses. We further use the insertion of poly-glycine motifs (Gly7) to decouple domains from one another and qualitatively show that, intrinsically, the sensor domain has a drastically poor ligand-dependent state transition propensity, and similarly, the autokinase domain has a drastically high basal kinase activity. The HAMP domain strongly couples to both domains and is sufficient to adjust these propensities to what is observed in the full length PhoQ. We suggest that signal transduction in PhoQ occurs by an allosteric coupling mechanism, in which the HAMP domain strongly couples to and acts in opposition the underlying signaling state equilibria of PhoQ such that it is maximally responsive to physiologically relevant ranges of stimuli. We demonstrate the same phenomenon in two other E. coli HAMP containing HKs, CpxA and BaeS, and suggest this may be a common theme in the evolution of signal transduction domains in HKs. In order to quantitatively examine the feasibility of modulating various ligand-dependent properties that inform HK function through evolution, we next establish and experimentally fit a three-domain, two-state equilibrium allosteric signaling model. We demonstrate that small changes to the HAMP domain sequence allow for robust modulation of the signaling ensemble and provide quantitative measures for the strong modulation of both sensor and autokinase domains by the HAMP, as well as the effects of point-mutations and Gly7 insertions. We more fully examine the ability of the HAMP to couple strongly and influence the sensor and autokinase domains of PhoQ by introducing a large library of variants in the HAMP four-helix bundle hydrophobic core, as well as the junction between the HAMP and autokinase domains (the S-Helix) and selecting for variants with high PhoQ activity. We find that destabilizing the HAMP four-helix bundle hydrophobic core does indeed lead to higher kinase activity. Furthermore, we find that the wild-type S-Helix sequence is enriched in the high-activity population, along with sequences with comparable polarity or poor helical propensity. Taken together, these observations lend credence to the hypothesis that the thermodynamically preferred signaling state of the HAMP behaves as a negative allosteric regulator of the autokinase, and that this regulation is alleviated by destabilizing the core helical bundle structure as well as the alpha-helical motif that connects it to the autokinase. We investigate this relationship further using a deep learning method to establish sequence-activity predictive relationships and extract structural features that are essential for this behavior. Finally, we examine the question of whether the HAMP domain exists in two distinct structural states, or rather conformational ensembles that can be classified into one of two functional states. We examine signaling through the HAMP domain of an E. coli histidine kinase, CpxA, by constructing a small library of structurally diverse inputs into the HAMP domain and evaluate the resulting autokinase activity as a function of several S-helix point mutations. This analysis allows us to discern the relationship between different signal inputs into the HAMP domain as the linkage to the output domain (autokinase) is varied. We find that the HAMP seems to have a multiconformational landscape that is not explained by 2 unique structural conformations.In this thesis, we show that the insertion of signal transduction domains in HKs can significantly alter both the intrinsic behaviors of sensor and autokinase domains, as well as the coupling between them. These properties can be well-described through a coupled two-state allosteric mechanism, and easily finetuned through simple mutations to the signal transduction domain and its linkage to adjacent domains to achieve the desired physiologically relevant activity profile.
- Published
- 2021
134. Targeted in vivo mutagenesis of a sensor histidine kinase playing an essential role in ABA signaling of the moss Physcomitrium patens
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Rahul Sk, Marcos Takeshi Miyabe, Daisuke Takezawa, Shunsuke Yajima, Izumi Yotsui, Teruaki Taji, and Yoichi Sakata
- Subjects
Histidine Kinase ,Mutagenesis ,Mutation ,Biophysics ,Cell Biology ,Ethylenes ,Molecular Biology ,Biochemistry ,Bryopsida ,Abscisic Acid - Abstract
Land plants exhibit various adaptation responses to unfavorable water environments, such as drought and flooding. The phytohormone abscisic acid (ABA) and ethylene play essential roles in plant adaptation to drought and flooding, respectively. It remains largely unknown how plants integrate environmental information for water availability. In the moss Physcomitrium patens, we recently reported that not only ethylene/flooding signaling but also ABA/osmostress signaling are mediated by ethylene receptor-related sensor histidine kinases (ETR-HKs). Subfamily I ETR-HKs of this moss were found to interact with a RAF kinase (ARK) and were required for ABA-dependent activation of SNF1-related protein kinase 2 (SnRK2) via ARK activation. To elucidate the mechanisms of ARK regulation by ETR-HKs, here we employed targeted in vivo mutagenesis of PpHK5, a member of subfamily I ETR-HKs. Analyses of ABA-insensitive Pphk5 mutants indicated that PpHK5 mutations affecting the interaction with ARK resulted in loss of PpHK5 function to activate ABA signaling. We also identified a PpHK5 mutation that does not affect ARK interaction but resulted in loss of PpHK5 function. These results suggest that physical interaction between ETR-HK and ARK is essential but not sufficient for the regulation of ARK activity, and the C-terminal response regulator domain is involved in regulating ARK activation.
- Published
- 2022
135. Mechanisms of E. coli chemotaxis signaling pathways visualized using cryoET and computational approaches
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Kyprianos Hadjidemetriou, Satinder Kaur, C. Keith Cassidy, and Peijun Zhang
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Electron Microscope Tomography ,Histidine Kinase ,Bacterial Proteins ,Chemotaxis ,Escherichia coli ,Methyl-Accepting Chemotaxis Proteins ,Biochemistry ,Signal Transduction - Abstract
Chemotaxis signaling pathways enable bacteria to sense and respond to their chemical environment and, in some species, are critical for lifestyle processes such as biofilm formation and pathogenesis. The signal transduction underlying chemotaxis behavior is mediated by large, highly ordered protein complexes known as chemosensory arrays. For nearly two decades, cryo-electron tomography (cryoET) has been used to image chemosensory arrays, providing an increasingly detailed understanding of their structure and function. In this mini-review, we provide an overview of the use of cryoET to study chemosensory arrays, including imaging strategies, key results, and outstanding questions. We further discuss the application of molecular modeling and simulation techniques to complement structure determination efforts and provide insight into signaling mechanisms. We close the review with a brief outlook, highlighting promising future directions for the field.
- Published
- 2022
136. The role of sensory kinase proteins in two-component signal transduction
- Author
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Adrián F. Alvarez and Dimitris Georgellis
- Subjects
Histidine Kinase ,Bacterial Proteins ,Phosphorylation ,Protein Kinases ,Biochemistry ,Signal Transduction - Abstract
Two-component systems (TCSs) are modular signaling circuits that regulate diverse aspects of microbial physiology in response to environmental cues. These molecular circuits comprise a sensor histidine kinase (HK) protein that contains a conserved histidine residue, and an effector response regulator (RR) protein with a conserved aspartate residue. HKs play a major role in bacterial signaling, since they perceive specific stimuli, transmit the message across the cytoplasmic membrane, and catalyze their own phosphorylation, and the trans-phosphorylation and dephosphorylation of their cognate response regulator. The molecular mechanisms by which HKs co-ordinate these functions have been extensively analyzed by genetic, biochemical, and structural approaches. Here, we describe the most common modular architectures found in bacterial HKs, and address the operation mode of the individual functional domains. Finally, we discuss the use of these signaling proteins as drug targets or as sensing devices in whole-cell biosensors with medical and biotechnological applications.
- Published
- 2022
137. Evolving a robust signal transduction pathway from weak cross-talk.
- Author
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Siryaporn, Albert, Perchuk, Barrett S, Laub, Michael T, and Goulian, Mark
- Subjects
Escherichia coli ,Protein Kinases ,Bacterial Proteins ,Bacterial Outer Membrane Proteins ,Escherichia coli Proteins ,Trans-Activators ,Directed Molecular Evolution ,Amino Acid Substitution ,Signal Transduction ,Gene Expression Regulation ,Bacterial ,Protein Binding ,Phosphorylation ,Mutation ,Protein Interaction Domains and Motifs ,cross-talk ,directed evolution ,histidine kinase ,synthetic biology ,Gene Expression Regulation ,Bacterial ,Bioinformatics ,Biochemistry and Cell Biology ,Other Biological Sciences - Abstract
We have evolved a robust two-component signal transduction pathway from a sensor kinase (SK) and non-partner response regulator (RR) that show weak cross-talk in vitro and no detectable cross-talk in vivo in wild-type strains. The SK, CpxA, is bifunctional, with both kinase and phosphatase activities for its partner RR. We show that by combining a small number of mutations in CpxA that individually increase phosphorylation of the non-partner RR OmpR, phosphatase activity against phospho-OmpR emerges. The resulting circuit also becomes responsive to input signal to CpxA. The effects of combining these mutations in CpxA appear to reflect complex intragenic interactions between multiple sites in the protein. However, by analyzing a simple model of two-component signaling, we show that the behavior can be explained by a monotonic change in a single parameter controlling protein-protein interaction strength. The results suggest one possible mode of evolution for two-component systems with bifunctional SKs whereby the remarkable properties and competing reactions that characterize these systems can emerge by combining mutations of the same effect.
- Published
- 2010
138. Transmembrane Prolines Mediate Signal Sensing and Decoding in Bacillus subtilis DesK Histidine Kinase
- Author
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Pilar Fernández, Lucía Porrini, Daniela Albanesi, Luciano A. Abriata, Matteo Dal Peraro, Diego de Mendoza, and María C. Mansilla
- Subjects
histidine kinase ,proline ,thermosensing ,two-component regulatory systems ,Microbiology ,QR1-502 - Abstract
ABSTRACT Environmental awareness is an essential attribute of all organisms. The homeoviscous adaptation system of Bacillus subtilis provides a powerful experimental model for the investigation of stimulus detection and signaling mechanisms at the molecular level. These bacteria sense the order of membrane lipids with the transmembrane (TM) protein DesK, which has an N-terminal sensor domain and an intracellular catalytic effector domain. DesK exhibits autokinase activity as well as phosphotransferase and phosphatase activities toward a cognate response regulator, DesR, that controls the expression of an enzyme that remodels membrane fluidity when the temperature drops below ∼30°C. Membrane fluidity signals are transmitted from the DesK sensor domain to the effector domain via rotational movements of a connecting 2-helix coiled coil (2-HCC). Previous molecular dynamic simulations suggested important roles for TM prolines in transducing the initial signals of membrane fluidity status to the 2-HCC. Here, we report that individual replacement of prolines in DesKs TM1 and TM5 helices by alanine (DesKPA) locked DesK in a phosphatase-ON state, abrogating membrane fluidity responses. An unbiased mutagenic screen identified the L174P replacement in the internal side of the repeated heptad of the 2-HCC structure that alleviated the signaling defects of every transmembrane DesKPA substitution. Moreover, substitutions by proline in other internal positions of the 2-HCC reestablished the kinase-ON state of the DesKPA mutants. These results imply that TM prolines are essential for finely tuned signal generation by the N-terminal sensor helices, facilitating a conformational control by the metastable 2-HCC domain of the DesK signaling state. IMPORTANCE Signal sensing and transduction is an essential biological process for cell adaptation and survival. Histidine kinases (HK) are the sensory proteins of two-component systems that control many bacterial responses to different stimuli, like environmental changes. Here, we focused on the HK DesK from Bacillus subtilis, a paradigmatic example of a transmembrane thermosensor suited to remodel membrane fluidity when the temperature drops below 30°C. DesK provides a tractable system for investigating the mechanism of transmembrane signaling, one of the majors interrogates in biology to date. Our studies demonstrate that transmembrane proline residues modulate the conformational switch of a 2-helix coiled-coil (2-HCC) structural motif that controls input-output in a variety of HK. Our results highlight the relevance of proline residues within sensor domains and could inspire investigations of their role in different signaling proteins.
- Published
- 2019
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139. Identification of possible Ser/Thr/Tyr phosphorylation sites in the fungal histidine kinase CaNik1p by peptide array technique
- Author
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Mohammed El-Mowafy and Ursula Bilitewski
- Subjects
Histidine kinase ,CaNik1p ,Peptide array ,Therapeutics. Pharmacology ,RM1-950 ,Pharmacy and materia medica ,RS1-441 ,Pharmaceutical industry ,HD9665-9675 - Abstract
CaNik1p is a histidine kinase (HK) that is present in Candida albicans. It was found to be a target for antifungal activities on the hyperosmotic glycerol pathway. The protein has two well-known phosphorylation sites (P-sites); His510 and Asp924, that were found to be crucial for maintaining the fungicidal sensitivity. Our previous work showed that the double mutated protein, in H510 and D924, was still possessing kinase activity. In this study, we aimed to identify additional possible P-sites in this HK. Therefore, we constructed a peptide array that covers the full length protein. Incubation of the purified His-tagged CaNik1p with the peptide array in the presence of radioactive ATP [γ-32P] revealed the possible P-sites in each peptide. We classified the peptides according to their intensities. Peptides bearing His510 and D924 showed either null or very weak intensities. The highest intensity was corresponding to the peptide containing the amino acid T994, while lower intensities were related mainly to serine and threonine residues and to lower extent to tyrosine amino acid. We could show for the first time the detection of additional P-sites in CaNik1p that might contribute in the signalling pathways of C. albicans. Moreover, the protocol used in this study allows for direct focusing and prediction of the possible Ser, Thr, and Tyr phosphoaccepting residues in the newly discovered kinases.
- Published
- 2018
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140. Phosphate signaling through alternate conformations of the PstSCAB phosphate transporter
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Ramesh K. Vuppada, Colby R. Hansen, Kirsta A. P. Strickland, Keilen M. Kelly, and William R. McCleary
- Subjects
Phosphate homeostasis ,Two-component signal transduction ,Histidine kinase ,ABC transporter ,Microbiology ,QR1-502 - Abstract
Abstract Background Phosphate is an essential compound for life. Escherichia coli employs a signal transduction pathway that controls the expression of genes that are required for the high-affinity acquisition of phosphate and the utilization of alternate sources of phosphorous. These genes are only expressed when environmental phosphate is limiting. The seven genes for this signaling pathway encode the two-component regulatory proteins PhoB and PhoR, as well as the high-affinity phosphate transporter PstSCAB and an auxiliary protein called PhoU. As the sensor kinase PhoR has no periplasmic sensory domain, the mechanism by which these cells sense environmental phosphate is not known. This paper explores the hypothesis that it is the alternating conformations of the PstSCAB transporter which are formed as part of the normal phosphate transport cycle that signal phosphate sufficiency or phosphate limitation. Results We tested two variants of PstB that are predicted to lock the protein in either of two conformations for their signaling output. We observed that the pstBQ160K mutant, predicted to reside in an inward-facing, open conformation signaled phosphate sufficiency whereas the pstBE179Q mutant, predicted to reside in an outward-facing, closed conformation signaled phosphate starvation. Neither mutant showed phosphate transport. Conclusions These results support the hypothesis that the alternating conformations of the PstSCAB transporter are sensed by PhoR and PhoU. This sensory mechanism thus controls the alternate autokinase and phospho-PhoB phosphatase activities of PhoR, which ultimately control the signaling state of the response regulator PhoB.
- Published
- 2018
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141. Two-Component Systems of S. aureus: Signaling and Sensing Mechanisms
- Author
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Lisa Bleul, Patrice Francois, and Christiane Wolz
- Subjects
S. aureus ,two-component systems ,histidine kinase ,signal sensing ,ligand ,Genetics ,QH426-470 - Abstract
Staphylococcus aureus encodes 16 two-component systems (TCSs) that enable the bacteria to sense and respond to changing environmental conditions. Considering the function of these TCSs in bacterial survival and their potential role as drug targets, it is important to understand the exact mechanisms underlying signal perception. The differences between the sensing of appropriate signals and the transcriptional activation of the TCS system are often not well described, and the signaling mechanisms are only partially understood. Here, we review present insights into which signals are sensed by histidine kinases in S. aureus to promote appropriate gene expression in response to diverse environmental challenges.
- Published
- 2021
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142. The Role of Dimorphism Regulating Histidine Kinase (Drk1) in the Pathogenic Fungus Paracoccidioides brasiliensis Cell Wall
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Marina Valente Navarro, Yasmin Nascimento de Barros, Wilson Dias Segura, Alison Felipe Alencar Chaves, Grasielle Pereira Jannuzzi, Karen Spadari Ferreira, Patrícia Xander, and Wagner Luiz Batista
- Subjects
histidine kinase ,dimorphism ,Paracoccidioides ,paracoccidioidomycosis ,cell wall ,Biology (General) ,QH301-705.5 - Abstract
Dimorphic fungi of the Paracoccidioides genus are the causative agents of paracoccidioidomycosis (PCM), an endemic disease in Latin America with a high incidence in Brazil. This pathogen presents as infective mycelium at 25 °C in the soil, reverting to its pathogenic form when inhaled by the mammalian host (37 °C). Among these dimorphic fungal species, dimorphism regulating histidine kinase (Drk1) plays an essential role in the morphological transition. These kinases are present in bacteria and fungi but absent in mammalian cells and are important virulence and cellular survival regulators. Hence, the purpose of this study was to investigate the role of PbDrk1 in the cell wall modulation of P. brasiliensis. We observed that PbDrk1 participates in fungal resistance to different cell wall-disturbing agents by reducing viability after treatment with iDrk1. To verify the role of PbDRK1 in cell wall morphogenesis, qPCR results showed that samples previously exposed to iDrk1 presented higher expression levels of several genes related to cell wall modulation. One of them was FKS1, a β-glucan synthase that showed a 3.6-fold increase. Furthermore, confocal microscopy analysis and flow cytometry showed higher β-glucan exposure on the cell surface of P. brasiliensis after incubation with iDrk1. Accordingly, through phagocytosis assays, a significantly higher phagocytic index was observed in yeasts treated with iDrk1 than the control group, demonstrating the role of PbDrk1 in cell wall modulation, which then becomes a relevant target to be investigated. In parallel, the immune response profile showed increased levels of proinflammatory cytokines. Finally, our data strongly suggest that PbDrk1 modulates cell wall component expression, among which we can identify β-glucan. Understanding this signalling pathway may be of great value for identifying targets of antifungal molecular activity since HKs are not present in mammals.
- Published
- 2021
- Full Text
- View/download PDF
143. Driving the catalytic activity of a transmembrane thermosensor kinase.
- Author
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Inda, María Eugenia, Almada, Juan Cruz, Vazquez, Daniela Belén, Bortolotti, Ana, Fernández, Ariel, Ruysschaert, Jean Marie, and Cybulski, Larisa Estefanía
- Subjects
- *
CATALYTIC activity , *CATALYTIC domains , *HIGH temperatures , *LOW temperatures , *TEMPERATURE sensors - Abstract
DesK is a Bacillus thermosensor kinase that is inactive at high temperatures but turns activated when the temperature drops below 25 °C. Surprisingly, the catalytic domain (DesKC) lacking the transmembrane region is more active at higher temperature, showing an inverted regulation regarding DesK. How does the transmembrane region control the catalytic domain, repressing activity at high temperatures, but allowing activation at lower temperatures? By designing a set of temperature minimized sensors that share the same catalytic cytoplasmic domain but differ in number and position of hydrogen-bond (H-bond) forming residues along the transmembrane helix, we are able to tune, invert or disconnect activity from the input signal. By favoring differential H-bond networks, the activation peak could be moved towards lower or higher temperatures. This principle may be involved in regulation of other sensors as environmental physicochemical changes or mutations that modify the transmembrane H-bond pattern can tilt the equilibrium favoring alternative conformations. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
144. Synthesis of histidine kinase inhibitors and their biological properties.
- Author
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Rosales‐Hurtado, Miyanou, Meffre, Patrick, Szurmant, Hendrik, and Benfodda, Zohra
- Subjects
KINASE inhibitors ,BENZIMIDAZOLES ,DRUG resistance in bacteria ,CELLULAR signal transduction ,ANTIBACTERIAL agents ,SALICYLANILIDES - Abstract
Infections caused by multidrug‐resistant bacteria represent a significant and ever‐increasing cause of morbidity and mortality. There is thus an urgent need to develop efficient and well‐tolerated antibacterials targeting unique cellular processes. Numerous studies have led to the identification of new biological targets to fight bacterial resistance. Two‐component signal transduction systems are widely employed by bacteria to translate external and cellular signals into a cellular response. They are ubiquitous in bacteria, absent in the animal kingdom and are integrated into various virulence pathways. Several chemical series, including isothiazolidones, imidazolium salts, benzoxazines, salicylanilides, thiophenes, thiazolidiones, benzimidazoles, and other derivatives deduced by different approaches have been reported in the literature to have histidine kinase (HK) inhibitory activity. In this review, we report on the design and the synthesis of these HKs inhibitors and their potential to serve as antibacterial agents. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
145. Low phosphatase activity of LiaS and strong LiaR-DNA affinity explain the unusual LiaS to LiaR in vivo stoichiometry.
- Author
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Jani, Shailee, Sterzenbach, Karen, Adatrao, Vijaya, Tajbakhsh, Ghazal, Mascher, Thorsten, and Golemi-Kotra, Dasantila
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- *
STOICHIOMETRY , *BACILLUS subtilis , *CELLULAR signal transduction , *OLIGOMERIZATION , *PHOSPHORYLATION - Abstract
Background: LiaRS mediates Bacillus subtilis response to cell envelope perturbations. A third protein, LiaF, has an inhibitory role over LiaRS in the absence of stimulus. Together, LiaF and LiaRS form a three-component system characterized by an unusual stoichiometry, a 4:1 ratio between LiaS and LiaR, the significance of which in the signal transduction mechanism of LiaRS is not entirely understood. Results: We measured, for the first time, the kinetics of the phosphorylation-dependent processes of LiaRS, the DNA-binding affinity of LiaR, and characterized the effect of phosphorylation on LiaR oligomerization state. Our study reveals that LiaS is less proficient as a phosphatase. Consequently, unspecific phosphorylation of LiaR by acetyl phosphate may be significant in vivo. This drawback is exacerbated by the strong interaction between LiaR and its own promoter, as it can drive LiaRS into losing grip over its own control in the absence of stimuli. These intrinsic, seemingly 'disadvantageous", attributes of LiaRS are likely overcome by the higher concentration of LiaS over LiaR in vivo, and a pro-phosphatase role of LiaF. Conclusions: Overall, our study shows that despite the conservative nature of two-component systems, they are, ultimately, tailored to meet specific cell needs by modulating the dynamics of interactions among their components and the kinetics of phosphorylation-mediated processes. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
146. Rational modulation of the enzymatic intermediates for tuning the phosphatase activity of histidine kinase HK853.
- Author
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Ji, Shixia, Luo, Liang, Li, Conggang, Liu, Maili, Liu, Yixiang, and Jiang, Ling
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CELLULAR signal transduction , *DRUG design , *BACTERIAL diseases , *HISTIDINE , *THERMOTOGA maritima , *PHOSPHATASES , *CONFORMATIONAL analysis - Abstract
Histidine kinase (HK) of two-component signal transduction system (TCS) is a potential drug target for treating bacterial infections, and most HKs are bifunctional. We have previously identified the HXXXT motif of HK in HisKA subfamily to perform the phosphatase activity, but the specific working mechanism of the threonine is not well understood. In this paper, we use the phosphate group analog BeF 3 − to capture the enzymatic intermediates between HK853 and RR468 from Thermotoga maritima during dephosphorylation, and demonstrate that the T264 site is essential for populating capable near attack conformers (NAC) between enzyme and substrate to facilitate catalysis. Importantly, mutations at this site can modulate the phosphatase activity of HK. Our results help to understand the TCS signal transduction mechanisms and provide a reference for drug design. • Capture the intermediate state of HK853 enzymatic reaction. • Construct HK853 mutants with different activities based on near attack conformation theory. • Clarify the cooperation between T and H in the H×××T motif. • Elucidate the important role of T264 in the formation of near attack conformation. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
147. The quest for osmosensors in plants.
- Author
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Nongpiur, Ramsong Chantre, Singla-Pareek, Sneh Lata, and Pareek, Ashwani
- Subjects
- *
HISTIDINE kinases , *RECEPTOR-like kinases , *PHOSPHOLIPASES , *PHOSPHOLIPASE C , *AQUAPORINS , *CALCIUM channels , *PROTEIN kinases - Abstract
Osmotic stress has severe effects on crop productivity. Since climate change is predicted to exacerbate this problem, the development of new crops that are tolerant to osmotic stresses, especially drought and salinity stress, is required. However, only limited success has been achieved to date, primarily because of the lack of a clear understanding of the mechanisms that facilitate osmosensing. Here, we discuss the potential mechanisms of osmosensing in plants. We highlight the roles of proteins such as receptor-like kinases, which sense stress-induced cell wall damage, mechanosensitive calcium channels, which initiate a calcium-induced stress response, and phospholipase C, a membrane-bound enzyme that is integral to osmotic stress perception. We also discuss the roles of aquaporins and membrane-bound histidine kinases, which could potentially detect changes in extracellular osmolarity in plants, as they do in prokaryotes and lower eukaryotes. These putative osmosensors have the potential to serve as master regulators of the osmotic stress response in plants and could prove to be useful targets for the selection of osmotic stress-tolerant crops. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
148. ESPP2: Study of Two component signal transduction systems in Desulfovibrio vulgaris Hildenborough
- Author
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Mukhopadhyay, Aindrila
- Subjects
Basic biological sciences ,Histidine Kinase ,Response regulator proteins ,D. vulgaris Hildenborough ,signal transduction systems - Published
- 2009
149. Turing-pattern model of scaffolding proteins that establish spatial asymmetry during the cell cycle of Caulobacter crescentus
- Author
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Xu, Chunrui, Tyson, John J., Cao, Yang, Xu, Chunrui, Tyson, John J., and Cao, Yang
- Abstract
The crescent-shaped bacterium Caulobacter crescentus divides asymmetrically into a sessile (stalked) cell and a motile (flagellated) cell. This dimorphic cell division cycle is driven by the asymmetric appearance of scaffolding proteins at the cell's stalk and flagellum poles. The scaffolding proteins recruit enzyme complexes that phosphorylate and degrade a master transcription factor, CtrA, and the abundance and phosphorylation state of CtrA control the onset of DNA synthesis and the differentiation of stalked and flagellated cell types. In this study, we use a Turing-pattern mechanism to simulate the spatiotemporal dynamics of scaffolding proteins in Caulobacter and how they influence the abundance and intracellular distribution of CtrA similar to P. Our mathematical model captures crucial features of wild-type and mutant strains and predicts the distributions of CtrA similar to P and signaling proteins in mutant strains. Our model accounts for Caulobacter polar morphogenesis and shows how spatial localization and phosphosignaling cooperate to establish asymmetry during the cell cycle.
- Published
- 2023
150. A Link between Virulence and Homeostatic Responses to Hypoxia during Infection by the Human Fungal Pathogen Cryptococcus neoformans
- Author
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Chun, Cheryl D, Liu, Oliver W, and Madhani, Hiten D
- Subjects
Microbiology ,Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Prevention ,Genetics ,Infectious Diseases ,Aetiology ,2.1 Biological and endogenous factors ,2.2 Factors relating to the physical environment ,Infection ,Amino Acid Sequence ,Animals ,Antifungal Agents ,Cryptococcosis ,Cryptococcus neoformans ,Disease Models ,Animal ,Female ,Fluconazole ,Gene Expression Regulation ,Fungal ,Histidine Kinase ,Homeostasis ,Humans ,Hypoxia ,Mice ,Mice ,Inbred Strains ,Molecular Sequence Data ,Mutation ,Protein Kinases ,Sterol Regulatory Element Binding Proteins ,Virulence ,Immunology ,Medical Microbiology ,Virology ,Medical microbiology - Abstract
Fungal pathogens of humans require molecular oxygen for several essential biochemical reactions, yet virtually nothing is known about how they adapt to the relatively hypoxic environment of infected tissues. We isolated mutants defective in growth under hypoxic conditions, but normal for growth in normoxic conditions, in Cryptococcus neoformans, the most common cause of fungal meningitis. Two regulatory pathways were identified: one homologous to the mammalian sterol-response element binding protein (SREBP) cholesterol biosynthesis regulatory pathway, and the other a two-component-like pathway involving a fungal-specific hybrid histidine kinase family member, Tco1. We show that cleavage of the SREBP precursor homolog Sre1-which is predicted to release its DNA-binding domain from the membrane-occurs in response to hypoxia, and that Sre1 is required for hypoxic induction of genes encoding for oxygen-dependent enzymes involved in ergosterol synthesis. Importantly, mutants in either the SREBP pathway or the Tco1 pathway display defects in their ability to proliferate in host tissues and to cause disease in infected mice, linking for the first time to our knowledge hypoxic adaptation and pathogenesis by a eukaryotic aerobe. SREBP pathway mutants were found to be a hundred times more sensitive than wild-type to fluconazole, a widely used antifungal agent that inhibits ergosterol synthesis, suggesting that inhibitors of SREBP processing could substantially enhance the potency of current therapies.
- Published
- 2007
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