Amino Acids

, Volume 37, Issue 3, pp 459–466 | Cite as

Evolution of prokaryotic two-component systems: insights from comparative genomics

  • David E. WhitworthEmail author
  • Peter J. A. Cock
Review Article


Two-component systems (TCSs) are diverse and abundant signal transduction pathways found predominantly in prokaryotes. This review focuses on insights into TCS evolution made possible by the sequencing of whole prokaryotic genomes. Typical TCSs comprise an autophosphorylating protein (a histidine kinase), which transfers a phosphoryl group onto an effector protein (a response regulator), thus modulating its activity. Histidine kinases and response regulators are usually found encoded as pairs of adjacent genes within a genome, with multiple examples in most prokaryotes. Recent studies have shed light on major themes of TCS evolution, including gene duplication, gene gain/loss, gene fusion/fission, domain gain/loss, domain shuffling and the emergence of complexity. Coupled with an understanding of the structural and biophysical properties of many TCS proteins, it has become increasingly possible to draw inferences regarding the functional consequences of such evolutionary changes. In turn, this increase in understanding has the potential to enhance both our ability to rationally engineer TCSs, and also allow us to more powerfully correlate TCS evolution with behavioural phenotypes and ecological niche occupancy.


Response regulator Histidine kinase Hybrid kinase Gene fusion Gene fission Evolution Recombination Duplication Domain 


  1. Alm E, Huang K, Arkin A (2006) The evolution of two-component systems in bacteria reveals different strategies for niche adaptation. PLoS Comp Biol 2:e143CrossRefGoogle Scholar
  2. Appleby JL, Parkinson JS, Bourret RB (1996) Signal transduction via the multi-step phosphorelay: not necessarily a road less traveled. Cell 86:845–848PubMedCrossRefGoogle Scholar
  3. Armitage JP (1999) Bacterial tactic responses. Adv Microb Physiol 41:229–289PubMedCrossRefGoogle Scholar
  4. Ashby MK (2004) Survey of the number of two-component response regulator genes in the complete and annotated genome sequences of prokaryotes. FEMS Microbiol Lett 231:277–281PubMedCrossRefGoogle Scholar
  5. Barakat M, Ortet P, Jourlin-Castelli C, Ansaldi M, Mejean V, Whitworth DE (2009) P2CS: a two-component system resource for prokaryotic signal transduction research (submitted)Google Scholar
  6. Bijlsma JJE, Groisman E (2003) Making informed decisions: regulatory interactions between two-component systems. Trends Microbiol 11:359–366PubMedCrossRefGoogle Scholar
  7. Burger L, van Nimwegen E (2008) Accurate prediction of protein–protein interactions from sequence alignments using a Bayesian method. Mol Syst Biol 4:165PubMedCrossRefGoogle Scholar
  8. Chen Y-T, Chang HY, Lu CL, Peng HL (2004) Evolutionary analysis of the two-component systems in Pseudomonas aeruginosa PAO1. J Mol Evol 59:725–737PubMedCrossRefGoogle Scholar
  9. Cock PJA (2009) Two-component regulation: modelling, predicting and identifying protein–protein interactions and assessing signalling networks of bacteria. Ph.D. Thesis, University of Warwick, UKGoogle Scholar
  10. Cock PJA, Whitworth DE (2007a) Evolution of prokaryotic two-component system signaling pathways: gene fusions and fissions. Mol Biol Evol 24:2355–2357PubMedCrossRefGoogle Scholar
  11. Cock PJA, Whitworth DE (2007b) Evolution of gene overlaps: relative reading frame bias in prokaryotic two-component system genes. J Mol Evol 64:457–462PubMedCrossRefGoogle Scholar
  12. Cock PJA, Whitworth DE (2009) Unpublished dataGoogle Scholar
  13. D’Souza M, Glass EM, Syed MH, Zhang Y, Rodriguez A, Maltsev N, Galperin MY (2007) Sentra: a database of signal transduction proteins for comparative genome analysis. Nucleic Acids Res 35:D271–D273PubMedCrossRefGoogle Scholar
  14. Fabret C, Feher VA, Hoch JA (1999) Two-component signal transduction in Bacillus subtilis: how one organism sees its world. J Bacteriol 181:1975–1983PubMedGoogle Scholar
  15. Galperin MY (2005) A census of membrane-bound and intracellular signal transduction proteins in bacteria: bacterial IQ, extroverts and introverts. BMC Microbiol 5:35PubMedCrossRefGoogle Scholar
  16. Galperin MY (2006) Structural classification of bacterial response regulators: diversity of output domains and domain combinations. J Bacteriol 188:4169–4182PubMedCrossRefGoogle Scholar
  17. Gao R, Mack TR, Stock AM (2007) Bacterial response regulators: versatile regulatory strategies from common domains. Trends Biochem Sci 32:225–234PubMedCrossRefGoogle Scholar
  18. Grebe TW, Stock JB (1999) The histidine protein kinase superfamily. Adv Microb Physiol 41:139–227PubMedCrossRefGoogle Scholar
  19. Higgs PI, Cho K, Evans LS, Whitworth DE, Zusman DR (2005) Four unusual two-component signal transduction homologs, RedC–RedF, are necessary for timely development in Myxococcus xanthus. J Bacteriol 187:8191–8195PubMedCrossRefGoogle Scholar
  20. Hinchliffe SJ, Howard SL, Huang YH, Clarke DJ, Wren BW (2008) The importance of the Rcs phosphorelay in the survival and pathogenesis of the enteropathogenic yersiniae. Microbiology 154:1117–1131PubMedCrossRefGoogle Scholar
  21. Hoch JA, Varughese KI (2001) Keeping signals straight in phosphorelay signal transduction. J Bacteriol 183:4941–4949PubMedCrossRefGoogle Scholar
  22. Hutchings MI, Hoskisson PA, Chandra G, Buttner MJ (2004) Sensing and responding to diverse extracellular signals? Analysis of the histidine kinases and response regulators of Streptomyces coelicolor A3(2). Microbiology 150:2795–2806PubMedCrossRefGoogle Scholar
  23. Kim D-J, Forst S (2001) Genomic analysis of the histidine kinase family in bacteria and archaea. Microbiology 147:1197–1212PubMedGoogle Scholar
  24. Koretke KK, Lupas AN, Warren PV, Rosenberg M, Brown JR (2000) Evolution of two-component signal transduction. Mol Biol Evol 17:1956–1970PubMedGoogle Scholar
  25. Lawrence J (1999) Selfish operons: the evolutionary impact of gene clustering in prokaryotes and eukaryotes. Curr Opin Genet Dev 9:642–648PubMedCrossRefGoogle Scholar
  26. Martiny AC, Coleman ML, Chisholm SW (2006) Phosphate acquisition genes in Prochlorococcus ecotypes: evidence for genome-wide adaptation. Proc Natl Acad Sci USA 103:12552–12557PubMedCrossRefGoogle Scholar
  27. Michel B (1999) Illegitimate recombination in bacteria. In: Charlebois RL (ed) Organization of the prokaryotic genome. ASM Press, Washington, pp 129–150Google Scholar
  28. Mizuno T (1997) Compilation of all genes encoding two-component phosphotransfer signal transducers in the genome of Escherichia coli. DNA Res 4:161–168PubMedCrossRefGoogle Scholar
  29. Mizuno T, Kaneko T, Tabata S (1996) Compilation of all genes encoding bacterial two-component signal transducers in the genome of the cyanobacterium, Synechocystis sp. strain PCC 6803. DNA Res 3:407–414PubMedCrossRefGoogle Scholar
  30. Moraleda-Muñoz A, Carrero-Lérida J, Pérez J, Muñoz-Dorado J (2003) Role of two novel two-component regulatory systems in development and phosphatase expression in Myxococcus xanthus. J Bacteriol 185:1376–1383PubMedCrossRefGoogle Scholar
  31. Pao GM, Saier MH Jr (1995) Response regulators of bacterial signal transduction systems: selective domain shuffling during evolution. J Mol Evol 40:136–154PubMedCrossRefGoogle Scholar
  32. Qian W, Han Z-J, He C (2008) Two-component signal transduction systems of Xanthomonas spp.: a lesson from genomics. Mol Plant–Microbe Interact 21:151–161PubMedCrossRefGoogle Scholar
  33. Robinson VL, Buckler DR, Stock AM (2000) A tale of two components: a novel kinase and a regulatory switch. Nat Struct Biol 7:626–633PubMedCrossRefGoogle Scholar
  34. Skerker JM, Prasol MS, Perchuk BS, Biondi EG, Laub MT (2005) Two-component signal transduction pathways regulating growth and cell cycle progression in a bacterium: a system-level analysis. PLoS Biol 3:e334PubMedCrossRefGoogle Scholar
  35. Skerker JM, Perchuk BS, Siryaporn A et al (2008) Rewiring the specificity of two-component signal transduction systems. Cell 133:1043–1054PubMedCrossRefGoogle Scholar
  36. Stephenson K, Hoch JA (2002) Evolution of signalling in the sporulation phosphorelay. Mol Microbiol 46:297–304PubMedCrossRefGoogle Scholar
  37. Stephenson K, Hoch JA (2004) Developing inhibitors to selectively target two-component and phosphorelay signal transduction systems of pathogenic microorganisms. Curr Med Chem 11:765–773PubMedCrossRefGoogle Scholar
  38. Stephenson K, Lewis RJ (2005) Molecular insights into the initiation of sporulation in Gram-positive bacteria: new technologies for an old phenomenon. FEMS Microbiol Rev 29:281–301PubMedCrossRefGoogle Scholar
  39. Stock JB, Ninfa AJ, Stock AM (1989) Protein phosphorylation and regulation of adaptive responses in bacteria. Microbiol Rev 53:450–490PubMedGoogle Scholar
  40. Thomas SA, Brewster JA, Bourret RB (2008) Two variable active site residues modulate response regulator phosphoryl group stability. Mol Microbiol 69:453–465PubMedCrossRefGoogle Scholar
  41. Tong ZZ, Zhou DS, Song YJ et al (2005) Genetic variations in the pgm locus among natural isolates of Yersinia pestis. J Gen Appl Microbiol 51:11–19PubMedCrossRefGoogle Scholar
  42. Ulrich LE, Zhulin IB (2007) MiST: a microbial signal transduction database. Nucleic Acids Res 35:D386–D390PubMedCrossRefGoogle Scholar
  43. Ulrich LE, Koonin EV, Zhulin IB (2005) One-component systems dominate signal transduction in prokaryotes. Trends Microbiol 31:52–56CrossRefGoogle Scholar
  44. Watanabe T, Okada A, Gotoh Y, Utsumi R (2008) Inhibitors targeting two-component signal transduction. Adv Exp Med Biol 631:229–236PubMedCrossRefGoogle Scholar
  45. Wegener-Feldbrügge S, Søgaard-Andersen L (2009) The atypical hybrid histidine protein kinase RodK in Myxococcus xanthus: spatial proximity supersedes kinetic preference in phosphotransfer reactions. J Bacteriol (in press) doi: 10.1128/JB.01405-08
  46. Weigt M, White RA, Szurmant H, Hoch JA, Hwa T (2009) Identification of direct residue contacts in protein–protein interaction by message passing. Proc Natl Acad Sci USA 106:67–72PubMedCrossRefGoogle Scholar
  47. Whitworth DE (2008) Genomes and knowledge—a questionable relationship? Trends Microbiol 16:512–519PubMedCrossRefGoogle Scholar
  48. Whitworth DE, Cock PJA (2008a) Two-component systems of the myxobacteria: structure, diversity and evolutionary relationships. Microbiology 154:360–372PubMedCrossRefGoogle Scholar
  49. Whitworth DE, Cock PJA (2008b) Myxobacterial two-component systems. In: Whitworth DE (ed) Myxobacteria: multicellularity and differentiation. ASM Press, Washington, pp 169–189Google Scholar
  50. Whitworth DE, Holmes AB, Irvine AG, Hodgson DA, Scanlan DJ (2008a) P-acquisition components of the Myxococcus xanthus Pho regulon are regulated by both P-availability and development. J Bacteriol 190:1997–2003PubMedCrossRefGoogle Scholar
  51. Whitworth DE, Millard A, Hodgson DA, Hawkins PF (2008b) Protein–protein interactions between two-component system transmitter and receiver domains of Myxococcus xanthus. Proteomics 8:1839–1842PubMedCrossRefGoogle Scholar
  52. Zhang W, Shi L (2005) Distribution and evolution of multiple-step phosphorelay in prokaryotes: lateral domain recruitment involved in the formation of hybrid-type histidine kinases. Microbiology 151:2159–2173PubMedCrossRefGoogle Scholar
  53. Zusman DR, Scott AE, Yang Z, Kirby JR (2007) Chemosensory pathways, motility and development in Myxococcus xanthus. Nat Rev Microbiol 5:862–872PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  1. 1.Institute of Biological, Environmental and Rural SciencesAberystwyth UniversityCeredigionUK
  2. 2.MOAC Doctoral Training Centre, Coventry HouseUniversity of WarwickCoventryUK

Personalised recommendations