Hysteretic and graded responses in bacterial two‐component signal transduction

Bacterial two‐component systems (TCS) are key signal transduction networks regulating global responses to environmental change. Environmental signals may modulate the phosphorylation state of sensor kinases (SK). The phosphorylated SK transfers the phosphate to its cognate response regulator (RR), which causes physiological response to the signal. Frequently, the SK is bifunctional and, when unphosphorylated, it is also capable of dephosphorylating the RR. The phosphatase activity may also be modulated by environmental signals. Using the EnvZ/OmpR system as an example, we constructed mathematical models to examine the steady‐state and kinetic properties of the network. Mathematical modelling reveals that the TCS can show bistable behaviour for a given range of parameter values if unphosphorylated SK and RR form a dead‐end complex that prevents SK autophosphorylation. Additionally, for bistability to exist the major dephosphorylation flux of the RR must not depend on the unphosphorylated SK. Structural modelling and published affinity studies suggest that the unphosphorylated SK EnvZ and the RR OmpR form a dead‐end complex. However, bistability is not possible because the dephosphorylation of OmpR∼P is mainly done by unphosphorylated EnvZ. The implications of this potential bistability in the design of the EnvZ/OmpR network and other TCS are discussed.

[1]  Akinori Kato,et al.  Connecting two-component regulatory systems by a protein that protects a response regulator from dephosphorylation by its cognate sensor. , 2004, Genes & development.

[2]  T. Mascher,et al.  Stimulus Perception in Bacterial Signal-Transducing Histidine Kinases , 2006, Microbiology and Molecular Biology Reviews.

[3]  D. Hilbert,et al.  Sporulation of Bacillus subtilis. , 2004, Current opinion in microbiology.

[4]  M. Thattai,et al.  Intrinsic noise in gene regulatory networks , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[5]  M. Inouye,et al.  Spontaneous subunit exchange and biochemical evidence for trans-autophosphorylation in a dimer of Escherichia coli histidine kinase (EnvZ). , 2003, Journal of molecular biology.

[6]  Gürol M. Süel,et al.  An excitable gene regulatory circuit induces transient cellular differentiation , 2006, Nature.

[7]  Torsten Schwede,et al.  BIOINFORMATICS Bioinformatics Advance Access published November 12, 2005 The SWISS-MODEL Workspace: A web-based environment for protein structure homology modelling , 2022 .

[8]  M A Savageau,et al.  Design of gene circuitry by natural selection: analysis of the lactose catabolic system in Escherichia coli. , 1999, Biochemical Society transactions.

[9]  D. Ritchie,et al.  Evaluation of Protein Docking Predictions Using Hex 3.1 in CAPRI Rounds 1{2 , 2002 .

[10]  J. Monod,et al.  General Conclusions: Teleonomic Mechanisms in Cellular Metabolism, Growth, and Differentiation , 1978 .

[11]  T. Silhavy,et al.  EnvZ controls the concentration of phosphorylated OmpR to mediate osmoregulation of the porin genes. , 1991, Journal of molecular biology.

[12]  J. Collins,et al.  Construction of a genetic toggle switch in Escherichia coli , 2000, Nature.

[13]  Eduardo Sontag,et al.  Untangling the wires: A strategy to trace functional interactions in signaling and gene networks , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[14]  Jeffrey M. Skerker,et al.  A phosphorelay system controls stalk biogenesis during cell cycle progression in Caulobacter crescentus , 2006, Molecular microbiology.

[15]  R. Utsumi,et al.  Functional Characterization in Vitro of All Two-component Signal Transduction Systems from Escherichia coli* , 2005, Journal of Biological Chemistry.

[16]  Michael A. Savageau,et al.  Design principles for elementary gene circuits: Elements, methods, and examples. , 2001, Chaos.

[17]  R. E. Huber,et al.  The action of beta-galactosidase (Escherichia coli) on allolactose. , 1975, Canadian journal of biochemistry.

[18]  R. E. Huber,et al.  The Action of β-Galactosidase (Escherichia coli) on Allolactose , 1975 .

[19]  J. Hoch,et al.  Evolution of signalling in the sporulation phosphorelay , 2002, Molecular microbiology.

[20]  P. Viollier,et al.  Cell cycle control by oscillating regulatory proteins in Caulobacter crescentus , 2006, BioEssays : news and reviews in molecular, cellular and developmental biology.

[21]  A. Ninfa,et al.  Development of Genetic Circuitry Exhibiting Toggle Switch or Oscillatory Behavior in Escherichia coli , 2003, Cell.

[22]  M. Surette,et al.  Active Site Interference and Asymmetric Activation in the Chemotaxis Protein Histidine Kinase CheA* , 1996, The Journal of Biological Chemistry.

[23]  J. Ferrell.  Self-perpetuating states in signal transduction: positive feedback, double-negative feedback and bistability. , 2002, Current opinion in cell biology.

[24]  T. S. Tropynina,et al.  Epigenes: design and construction of new hereditary units , 2000, FEBS letters.

[25]  S. Leibler,et al.  Phenotypic Diversity, Population Growth, and Information in Fluctuating Environments , 2005, Science.

[26]  Mark Goulian,et al.  Continuous Control in Bacterial Regulatory Circuits , 2004, Journal of bacteriology.

[27]  E. Calva,et al.  Two-Component Signal Transduction Systems, Environmental Signals, and Virulence , 2006, Microbial Ecology.

[28]  D. Kaiser,et al.  Evolution of sensory complexity recorded in a myxobacterial genome , 2006, Proceedings of the National Academy of Sciences.

[29]  T. Mizuno.  Two-Component Phosphorelay Signal Transduction Systems in Plants: from Hormone Responses to Circadian Rhythms , 2005, Bioscience, biotechnology, and biochemistry.

[30]  Martin Fussenegger,et al.  Hysteresis in a synthetic mammalian gene network. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[31]  Farren J. Isaacs,et al.  Prediction and measurement of an autoregulatory genetic module , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[32]  S. C. Winans,et al.  Unwounded plants elicit Agrobacterium vir gene induction and T‐DNA transfer: transformed plant cells produce opines yet are tumour free , 2005, Molecular microbiology.

[33]  Y. Sadaie,et al.  Feedback loops involving Spo0A and AbrB in in vitro transcription of the genes involved in the initiation of sporulation in Bacillus subtilis. , 1998, Journal of biochemistry.

[34]  Manuel C. Peitsch,et al.  SWISS-MODEL: an automated protein homology-modeling server , 2003, Nucleic Acids Res..

[35]  M. Thattai,et al.  Stochastic Gene Expression in Fluctuating Environments , 2004, Genetics.

[36]  Oscar P Kuipers,et al.  Phosphatases modulate the bistable sporulation gene expression pattern in Bacillus subtilis , 2005, Molecular microbiology.

[37]  Philippe Glaser,et al.  Aspartyl‐phosphate phosphatases deactivate the response regulator components of the sporulation signal transduction system in Bacillus subtilis , 1996, Molecular microbiology.

[38]  M. Inouye,et al.  EnvZ-OmpR Interaction and Osmoregulation in Escherichia coli * , 2002, The Journal of Biological Chemistry.

[39]  N. Brown,et al.  Molecular Microbiology , 1998, NATO ASI Series.

[40]  Oleg A Igoshin,et al.  Transient heterogeneity in extracellular protease production by Bacillus subtilis , 2008, Molecular systems biology.

[41]  A. Ninfa,et al.  Mechanism of the PII-activated phosphatase activity of Escherichia coli NRII (NtrB): how the different domains of NRII collaborate to act as a phosphatase. , 2003, Biochemistry.

[42]  Rui Alves,et al.  Comparative analysis of prototype two‐component systems with either bifunctional or monofunctional sensors: differences in molecular structure and physiological function , 2003, Molecular microbiology.

[43]  B. Kholodenko,et al.  Signaling switches and bistability arising from multisite phosphorylation in protein kinase cascades , 2004, The Journal of cell biology.

[44]  J. Collins,et al.  Programmable cells: interfacing natural and engineered gene networks. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[45]  J. Monod,et al.  Teleonomic mechanisms in cellular metabolism, growth, and differentiation. , 1961, Cold Spring Harbor symposia on quantitative biology.

[46]  L. Kenney,et al.  Phosphorylation Alters the Interaction of the Response Regulator OmpR with Its Sensor Kinase EnvZ* , 2002, The Journal of Biological Chemistry.

[47]  David A. Drubin,et al.  Rational design of memory in eukaryotic cells. , 2007, Genes & development.

[48]  R. Losick,et al.  Bistability in bacteria , 2006, Molecular microbiology.

[49]  M. Inouye,et al.  Interaction of EnvZ, a sensory histidine kinase, with phosphorylated OmpR, the cognate response regulator , 2002, Molecular microbiology.

[50]  M. Inouye,et al.  Formation of the stoichiometric complex of EnvZ, a histidine kinase, with its response regulator, OmpR , 2002, Molecular microbiology.

[51]  D. Dubnau,et al.  Bistability in the Bacillus subtilis K‐state (competence) system requires a positive feedback loop , 2005, Molecular microbiology.

[52]  M. Goulian,et al.  Robustness and the cycle of phosphorylation and dephosphorylation in a two-component regulatory system , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[53]  J. Hoch,et al.  Protein aspartate phosphatases control the output of two-component signal transduction systems. , 1996, Trends in genetics : TIG.

[54]  Haruki Nakamura,et al.  The worldwide Protein Data Bank (wwPDB): ensuring a single, uniform archive of PDB data , 2006, Nucleic Acids Res..

[55]  D. Dubnau,et al.  Noise in Gene Expression Determines Cell Fate in Bacillus subtilis , 2007, Science.

[56]  T. Mascher.  Intramembrane-sensing histidine kinases: a new family of cell envelope stress sensors in Firmicutes bacteria. , 2006, FEMS microbiology letters.

[57]  M. Inouye,et al.  Ligand binding to the receptor domain regulates the ratio of kinase to phosphatase activities of the signaling domain of the hybrid Escherichia coli transmembrane receptor, Taz1. , 1993, Journal of molecular biology.

[58]  M. Surette,et al.  Dimerization Is Required for the Activity of the Protein Histidine Kinase CheA That Mediates Signal Transduction in Bacterial Chemotaxis (*) , 1996, The Journal of Biological Chemistry.

[59]  A. Novick,et al.  THE PROPERTIES OF REPRESSOR AND THE KINETICS OF ITS ACTION. , 1965, Journal of molecular biology.

[60]  M. Feinberg,et al.  Understanding bistability in complex enzyme-driven reaction networks. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[61]  M. Goulian,et al.  A simple system for converting lacZ to gfp reporter fusions in diverse bacteria. , 2006, Gene.

[62]  R. Thomas,et al.  Positive feedback loops and multistationarity , 1988, Discret. Appl. Math..

[63]  R. Gross,et al.  Regulation of bacterial virulence by two-component systems. , 2006, Current opinion in microbiology.

[64]  B. Séraphin,et al.  Positive feedback in eukaryotic gene networks: cell differentiation by graded to binary response conversion , 2001, The EMBO journal.

[65]  Mark Ptashne,et al.  A Genetic Switch, Phage Lambda Revisited , 2004 .

[66]  M. Inouye,et al.  Probing catalytically essential domain orientation in histidine kinase EnvZ by targeted disulfide crosslinking. , 2003, Journal of molecular biology.

[67]  J. Hoch,et al.  Transition‐state regulators: sentinels of Bacillus subtilis post‐exponential gene expression , 1993, Molecular microbiology.

[68]  M. Inouye,et al.  The critical role of DNA in the equilibrium between OmpR and phosphorylated OmpR mediated by EnvZ in Escherichia coli. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[69]  Michael A Savageau,et al.  Signalling network with a bistable hysteretic switch controls developmental activation of the σF transcription factor in Bacillus subtilis , 2006, Molecular microbiology.

[70]  A. Ninfa,et al.  Asymmetry in the autophosphorylation of the two-component regulatory system transmitter protein nitrogen regulator II of Escherichia coli. , 2000, Biochemistry.

[71]  Michael T Laub,et al.  Two-Component Signal Transduction Pathways Regulating Growth and Cell Cycle Progression in a Bacterium: A System-Level Analysis , 2005, PLoS biology.

[72]  Ellen M. Quardokus,et al.  Mutations in DivL and CckA Rescue a divJ Null Mutant of Caulobacter crescentus by Reducing the Activity of CtrA , 2006, Journal of bacteriology.

[73]  J. S. Parkinson,et al.  Bacterial Chemotaxis: a New Player in Response Regulator Dephosphorylation , 2003, Journal of bacteriology.

[74]  Ann M Stock,et al.  Two-component signal transduction. , 2000, Annual review of biochemistry.

[75]  S. Inouye,et al.  A novel regulation on developmental gene expression of fruiting body formation in Myxobacteria , 2006, Applied Microbiology and Biotechnology.

[76]  Barry L. Wanner,et al.  Kinetic Comparison of the Specificity of the Vancomycin Resistance Kinase VanS for Two Response Regulators, VanR and PhoB† , 1996 .

[77]  T. Mizuno,et al.  His-Asp phosphotransfer signal transduction. , 1998, Journal of biochemistry.

[78]  J. Hoch,et al.  Spo0A activates and represses its own synthesis by binding at its dual promoters. , 1992, Biochimie.

[79]  Ertugrul M. Ozbudak,et al.  Regulation of noise in the expression of a single gene , 2002, Nature Genetics.

[80]  A. Ninfa,et al.  Functional dissection of the dimerization and enzymatic activities of Escherichia coli nitrogen regulator II and their regulation by the PII protein. , 2000, Biochemistry.

[81]  A. Novick,et al.  ENZYME INDUCTION AS AN ALL-OR-NONE PHENOMENON. , 1957, Proceedings of the National Academy of Sciences of the United States of America.

[82]  C. Walsh,et al.  Purification and characterization of VanR and the cytosolic domain of VanS: a two-component regulatory system required for vancomycin resistance in Enterococcus faecium BM4147. , 1993, Biochemistry.

[83]  M. Inouye,et al.  Phosphatase activity of histidine kinase EnvZ without kinase catalytic domain. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[84]  S. Bourgeois,et al.  lac Repressor-operator interaction. VI. The natural inducer of the lac operon. , 1972, Journal of molecular biology.

[85]  M. Sternberg,et al.  Enhanced genome annotation using structural profiles in the program 3D-PSSM. , 2000, Journal of molecular biology.

[86]  J. Hoch,et al.  Keeping Signals Straight in Phosphorelay Signal Transduction , 2001, Journal of bacteriology.

[87]  T. Elston,et al.  Stochasticity in gene expression: from theories to phenotypes , 2005, Nature Reviews Genetics.

[88]  M. Surette,et al.  Signal transduction in bacterial chemotaxis , 1992, The Journal of biological chemistry.

[89]  T. Silhavy,et al.  The essential tension: opposed reactions in bacterial two-component regulatory systems. , 1993, Trends in microbiology.