Abstract
Response regulators of bacterial sensory transduction systems generally consist of receiver module domains covalently linked to effector domains. The effector domains include DNA binding and/or catalytic units that are regulated by sensor kinase-catalyzed aspartyl phosphorylation within their receiver modules. Most receiver modules are associated with three distinct families of DNA binding domains, but some are associated with other types of DNA binding domains, with methylated chemotaxis protein (MCP) demethylases, or with sensor kinases. A few exist as independent entities which regulate their target systems by noncovalent interactions.
In this study the molecular phylogenies of the receiver modules and effector domains of 49 fully sequenced response regulators and their homologues were determined. The three major, evolutionarily distinct, DNA binding domains found in response regulators were evaluated for their phylogenetic relatedness, and the phylogenetic trees obtained for these domains were compared with those for the receiver modules. Members of one family (family 1) of DNA binding domains are linked to large ATPase domains which usually function cooperatively in the activation of E. Coli σ54-dependent promoters or their equivalents in other bacteria. Members of a second family (family 2) always function in conjunction with the E. Coli σ70 or its equivalent in other bacteria. A third family of DNA binding domains (family 3) functions by an uncharacterized mechanism involving more than one a factor. These three domain families utilize distinct helix-turn-helix motifs for DNA binding.
The phylogenetic tree of the receiver modules revealed three major and several minor clusters of these domains. The three major receiver module clusters (clusters 1, 2, and 3) generally function with the three major families of DNA binding domains (families 1, 2, and 3, respectively) to comprise three classes of response regulators (classes 1, 2, and 3), although several exceptions exist. The minor clusters of receiver modules were usually, but not always, associated with other types of effector domains. Finally, several receiver modules did not fit into a cluster. It was concluded that receiver modules usually diverged from common ancestral protein domains together with the corresponding effector domains, although domain shuffling, due to intragenic splicing and fusion, must have occurred during the evolution of some of these proteins.
Multiple sequence alignments of the 49 receiver modules and their various types of effector domains, together with other homologous domains, allowed definition of regions of striking sequence similarity and degrees of conservation of specific residues. Sequence data were correlated with structure/function when such information was available. These studies should provide guides for extrapolation of results obtained with one response regulator to others as well as for the design of future structure/function analyses.
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References
Amster-Choder O, Wright A (1993) Transcriptional regulation of the bgl operon of E. coli involves PTS-mediated phosphorylation of a transcriptional antiterminator. J Cell Biochem 51:83–90
Blumer KJ, Johnson GL (1994) Diversity in function and regulation of MAP kinase pathways. TIBS 19:236–240
Bourret RB, Borkovich KA, Simon MI (1991) Signal transduction pathways involving protein phosphorylation in prokaryotes. Annu Rev Biochem 60:401–441
Bourret RB, Drake SK, Chervitz SA, Simon MI, Falke JJ (1993) Activation of the phosphosignaling protein CheY. II. Analysis of activated mutants by 19F NMR and protein engineering. J Biol Chem 268:13089–13096
Chang C, Meyerowitz EM (1994) Eukaryotes have “two-component” signal transducers. Res Microbiol 145:481–486
Cornish EC, Argyropoulos VP, Pittard J, Davidson B (1986) Structure of the Escherichia coli K12 regulatory gene tyrR. Nucleotide sequence and sites of initiation of transcription and translation. J Biol Chem 261:403–410
Cui J, Ni L, Somerville RL (1993) ATPase activity of TyrR, a transcriptional regulatory protein for σ70 RNA polymerase. J Biol Chem 268:13023–13025
Davis RJ (1993) The Mitogen-activated protein kinase signal transduction pathway. J Biol Chem 268:14553–14556
Débarbouillé M, Martin-Verstraete I, Klier A, Rapoport G (1991a) The transcriptional regulator LevR of Bacillus subtilis has domains homologous to both sigma-54 and phosphotransferase system-dependent regulators. Proc Natl Acad Sci USA 88:2212–2216
Débarbouillé M, Martin-Verstraete I, Kunst F, Rapoport G (1991b) The Bacillus subtilis sigL gene encodes an equivalent of σ54 from Gram-negative bacteria. Proc Natl Acad Sci USA 88:9092–9096
Drake SK, Bourret RB, Luck LA, Simon MI, Falke JJ (1993) Activation of the phosphosignaling protein CheY. I. Analysis of the phosphorylated conformation by 19F NMR and protein engineering. J Biol Chem 268:13081–13088
Feng D-F, Doolittle RF (1990) Progressive alignment and phylogenetic tree construction cf protein sequences. Methods Enzymol 183:375–387
Fischer EH (1993) Protein phosphorylation and cellular regulation II (Nobel Lecture). Angew Chem Int Ed Engl 32:1130–1137
Gross R (1993) Signal transduction and virulence regulation in human and animal pathogens. FEMS Microbiol Rev 104:301–326
Gross R, Arico B, Rappouli R (1989) Families of bacterial signal transducing proteins. Mol Microbiol 3:1661–1667
Hamblin MJ, Shaw JG, Kelly DJ (1993) Sequence analysis and interposon mutagenesis of a sensor-kinase (DctS) and response-regulator (DctR) controlling synthesis of the high-affinity C4-dicarboxylate transport system in Rhodobacter capsulatus. Mol Gen Genet 237:215–224
Hanks SK, Quinn AM, Hunter T (1988) The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science 241:42–52
Hanks SK, Quinn AM (1991) Protein kinase catalytic domain sequence database: identification of conserved features of primary structure and classification of family members. In: Colowick SP, Kaplan NO (eds) Methods in enzymology, vol 200. Academic Press, Inc., New York, pp 38–63
Harrison SC (1991) A structural taxonomy of DNA-binding domains. Nature 353:715–719
Hazelbauer GL, Berg HC, Matsumura P (1993) Bacterial motility and signal transduction. Cell 73:15–22
Hoch JA (1993) The phosphorelay signal transduction pathway in the initiation of Bacillus subtilis sporulation. J Cell Biochem 51:55–61
Hofmann F, Dostmann W, Keilbach A, Landgraf W, Ruth P (1992) Structure and physiological role of cGMP-dependent protein kinase. Biochim Biophys Acta 1135:51–60
Hughes DA (1994) Histidine kinases hog the limelight. Nature 369:187–188
Hunter T (1991)Protein kinase classification. In: Colowick SP, Kaplan NO (eds) Methods in enzymology, vol 200. Academic Press, Inc., New York, pp 3–37
Kostrewa D, Granzin J, Koch C, Choe H-W, Raghunathan S, Wolf W, Labahn J, Kahmann R, Saenger W (1991) Three-dimensional structure of the E. coli DNA-binding protein FIS. Nature 349:178–180
Krebs EG (1993) Protein phosphorylation and cellular regulation 1 (Nobel Lecture). Angew Chem Int Ed Engl 32:1122–1129
Kyte J, Doolittle RF (1982) A simple method for displaying the hydropathic character of a protein. J Mol Biol 157:105–132
LaPorte DC (1993) The isocitrate dehydrogenase phosphorylation cycle: regulation and enzymology. J Cell Biochem 51:14–18
Lengeler JW, Bockmann J, Heuel H, Titgemeyer F (1992) The enzymes II of the PTS as carbohydrate transport systems: what the evolutionary studies tell us on their structure and function. In: Quagliariello E, Palmieri F (eds) Molecular mechanisms of transport. Elsevier Science, New York, pp 77–85
Lindberg RA, Quinn AM, Hunter T (1992) Dual-specificity protein kinases: will any hydroxyl do? TIBS 17:114–119
Lukat GS, Stock JB (1993) Response regulation in bacterial chemotaxis. J Cell Biochem 51:41–46
Lukat GS, Lee BH, Mottonen JM, Stock AM, Stock JB (1991) Roles of the highly conserved aspartate and lysine residues in the response regulator of bacterial chemotaxis. J Biol Chem 266:8348–8354
Maeda T, Wurgler-Murphy SM, Saito H (1994) A two-component system that regulates an osmosensing MAP kinase cascade in yeast. Nature 369:242–245
Magasanik B (1993) The regulation of nitrogen utilization in enteric bacteria. J Cell Biochem 51:34–40
McDermott TR, Griffith SM, Vance CP, Graham PH (1989) Carbon metabolism in Bradyrhizobium japonicum bacteroids. FEMS Microbiol Rev 63:327–340
Munoz-Dorado J, Inouye S, Inouye M (1993) Eukaryotic-like protein serine/threonine kinases in Myxococcus xanthus, a developmental bacterium exhibiting social behavior. J Cell Biochem 51:29–33
Neiman AM (1993) Conservation and reiteration of a kinase cascade. Trends Genet 9:390–394
North AK, Klose KE, Stedman KM, Kustu S (1993) Prokaryotic enhancer-binding proteins reflect eukaryote-like modularity: the puzzle of nitrogen regulatory protein C. J Bacteriol 175:4267–4273
Pao GM, Tam R, Lipschitz LS, Saier MH, Jr (1994) Response regulators: structure, function and evolution. Res Microbiol 145:356–362
Parkinson JS, Kofoid EC (1992) Communication modules in bacterial signaling proteins. Annu Rev Genet 26:71–112
Pittard AJ, Davidson BE (1991) TyrR protein of Escherichia coli and its role as repressor and activator. Mol Microbiol 5:1585–1592
Popham DL, Szeto D, Keener J, Kustu S (1989) Function of a bacterial activator protein that binds to transcriptional enhancers. Science 243:629–635
Reizer A, Pao GM, Saier MH Jr (1991) Evolutionary relationships among the permease proteins of the bacterial phosphoenolpyruvate: sugar phosphotransferase system. Construction of phylogenetic trees and possible relatedness to proteins of eukaryotic mitochondria. J Mol Evol 33:179–193
Reizer J, Romano AH, Deutscher J (1993) The role of phosphorylation of HPr, a phosphocarrier protein of the phosphotransferase system, in the regulation of carbon metabolism in Gram-positive bacteria. J Cell Biochem 51:19–24
Richet E, Raibaud O (1989) MaIT,the regulatory protein of the Escherichia coli maltose system, is an ATP-dependent transcriptional activator. EMBO J 8:981–987
Saier MH Jr (1979) The role of the cell surface in regulating the internal environment. In: The bacteria, vol VII, Chapter 4. Academic Press, Inc., pp 167–227
Saier MH Jr (1993a) Protein phosphorylation and signal transduction in bacteria: an introduction. J Cell Biochem 51:1–6
Saier MH Jr (1993b) Regulatory interactions involving the proteins of the bacterial phosphotransferase system in enteric bacteria. J Cell Biochem 51:62–68
Saier MH Jr (1994) Bacterial sensor kinase/response regulator systems: an introduction. Res Microbiol 145:349–355
Saier MH Jr, Wu L-F, Reizer J (1990) Regulation of bacterial physiological processes by three types of protein phosphorylating systems. TIBS 15:391–395
Shabb JB, Corbin JD (1992) Cyclic nucleotide-binding domains in proteins having diverse functions. J Biol Chem 267:5723–5726
Stock JB, Ninfa AJ, Stock AM (1989) Protein phosphorylation and regulation of adaptive responses in bacteria. Microbiol Rev 53:450–490
Stock JB, Stock AM, Mottonen JM (1990) Signal transduction in bacteria. Nature 344:395–400
Strauch MA, Hoch JA (1992) Sporulation in prokaryotes and lower eukaryotes. Curr Opin Genet Dev 2:799–804
Tam R, Saier MH Jr (1993) Structural, functional, and evolutionary relationships among extracellular solute-binding receptors of bacteria. Microbiol Rev 57:320–346
Taylor SS (1989) CAMP-dependent protein kinase. J Biol Chem 264: 8443–8446
Volz K (1993) Conservation in the CheY superfamily. Biochem 32: 11741–11753
Volz K, Matsummura P (1991) Crystal structure of Escherichia coli CheY refined at 1.7 Å resolution. J Biol Chem 266:15511–15519
Wanner BL (1993) Gene regulation by phosphate in enteric bacteria. J Cell Biochem 51:47–54
Weiss DS, Batut J, Klose KE, Keener J, Kustu S (1991) The phosphorylated form of the enhancer-binding protein NTRC has an ATPase activity that is essential for activation of transcription. Cell 67:155–167
Wu L-F, Tomich JM, Saier MH Jr (1989) Structure and evolution of a multidomain multiphosphoryl transfer protein. Nucleotide sequence of the fruB(HI) gene in Rhodobacter capsulatus and comparisons with homologous genes from other organisms. J Mol Biol 213:687–703
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Correspondence to: M.H. Saier, Jr.
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Pao, G.M., Saier, M.H. Response regulators of bacterial signal transduction systems: Selective domain shuffling during evolution. J Mol Evol 40, 136–154 (1995). https://doi.org/10.1007/BF00167109
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DOI: https://doi.org/10.1007/BF00167109