Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

A tale of two components: a novel kinase and a regulatory switch

Nature Structural Biology volume 7, pages 626–633 (2000)Cite this article

Abstract

Histidine protein kinases and response regulators form the basis of phosphotransfer signal transduction pathways. Commonly referred to as two-component systems, these modular and adaptable signaling schemes are prevalent in prokaryotes. Structures of the core domains of histidine kinases reveal a protein kinase fold different from that of the Ser/Thr/Tyr protein kinase family, but similar to that of other ATP binding domains. Recent structure determinations of phosphorylated response regulator domains indicate a conserved mechanism for the propagated conformational change that accompanies phosphorylation of an active site Asp residue. The altered molecular surface promotes specific protein–protein interactions that mediate the downstream response.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Modular domains involved in two-component signal transduction.
Figure 2: Two members of the HK/ATPase structural family.
Figure 3: HK and HPt domains.
Figure 4: Conserved mechanism for propagation of the conformational changes associated with phosphorylation of the RR regulatory domain.
Figure 5: Conformational changes in activated RR regulatory domains.
Figure 6: Multidomain RR proteins.

Similar content being viewed by others

References

  1. Stock, A., Koshland, D.E., Jr. & Stock, J. Homologies between the Salmonella typhimurium CheY protein and proteins involved in the regulation of chemotaxis, membrane protein synthesis, and sporulation. Proc. Natl. Acad. Sci. USA 82, 7989–7993 (1985).

    Article  CAS  Google Scholar 

  2. Nixon, B.T., Ronson, C.W. & Ausubel, F.M. Two-component regulatory systems responsive to environmental stimuli share strongly conserved domains with the nitrogen assimilation regulatory genes ntrB and ntrC. Proc. Natl. Acad. Sci. USA 83, 7850–7854 (1986).

    Article  CAS  Google Scholar 

  3. Stock, J.B., Surette, M.G., Levit, M. & Park, P. In Two-component signal transduction (eds, Hoch, J.A. & Silhavy, T.J.), 25–51 (American Society for Microbiology, Washington, DC; 1995).

    Google Scholar 

  4. Stock, A.M., Robinson, V.L. & Goudreau, P.N. Two-component signal transduction. Annu. Rev. Biochem. 69, 183–215 (2000).

    Article  CAS  Google Scholar 

  5. Mizuno, T. Compilation of all genes encoding two-component phosphotransfer signal transducers in the genome of Escherichia coli. DNA Res. 4, 161–168 (1997).

    Article  CAS  Google Scholar 

  6. Throup, J.P. et al. A genomic analysis of two-component signal transduction in Streptococcus pneumoniae. Mol. Microbiol. 35, 566–576 (2000).

    Article  CAS  Google Scholar 

  7. Fabret, C., Feher, V.A. & Hoch, J.A. Two-component signal transduction in Bacillus subtilis: how one organism sees its world. J. Bacteriol. 181, 1975–1983 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Smith, D.R. et al. Complete genome sequence of Methanobacterium thermoautotrophicum deltaH: functional analysis and comparative genomics. J. Bacteriol. 179, 7135–7155 (1997).

    Article  CAS  Google Scholar 

  9. Mizuno, T. His-Asp phosphotransfer signal transduction. J. Biochem. 123, 555–563 (1998).

    Article  CAS  Google Scholar 

  10. Chang, C. & Stewart, R.C. The two-component system. Regulation of diverse signaling pathways in prokaryotes and eukaryotes. Plant Physiol. 117, 723–731 (1998).

    Article  CAS  Google Scholar 

  11. Perraud, A.-L., Weiss, V. & Gross, R. Signalling pathways in two-component phosphorelay systems. Trends Microbiol. 7, 115–120 (1999).

    Article  CAS  Google Scholar 

  12. Falke, J.J., Bass, R.B., Butler, S.L., Chervitz, S.A. & Danielson, M.A. The two-component signaling pathway of bacterial chemotaxis: a molecular view of signal transduction by receptors, kinases, and adaptation enzymes. Annu. Rev. Cell Dev. Biol. 13, 457–512 (1997).

    Article  CAS  Google Scholar 

  13. Maeda, T., Wurgler-Murphy, S.M. & Saito, H. A two-component system that regulates an osmosensing MAP kinase cascade in yeast. Nature 369, 242–245 (1994).

    Article  CAS  Google Scholar 

  14. Thomason, P.A. et al. An intersection of the cAMP/PKA and two-component signal transduction systems in Dictyostelium. EMBO J. 17, 2838–2845 (1998).

    Article  CAS  Google Scholar 

  15. Bilwes, A.M., Alex, L.A., Crane, B.R. & Simon, M.I. Structure of CheA, a signal-transducing histidine kinase. Cell 96, 131–141 (1999).

    Article  CAS  Google Scholar 

  16. Tomomori, C. et al. Solution structure of the homodimeric core domain of Escherichia coli histidine kinase EnvZ. Nature Struct. Biol. 6, 729–734 (1999).

    Article  CAS  Google Scholar 

  17. Tanaka, T. et al. NMR structure of the histidine kinase domain of the E. coli osmosensor EnvZ. Nature 396, 88–92 (1998).

    Article  CAS  Google Scholar 

  18. Birck, C. et al. Conformational changes induced by phosphorylation of the FixJ receiver domain. Structure Fold. Des. 7, 1505–1515 (1999).

    Article  CAS  Google Scholar 

  19. Kern, D. et al. Structure of a transiently phosphorylated switch in bacterial signal transduction. Nature 402, 894–898 (1999).

    Article  CAS  Google Scholar 

  20. Lewis, R.J., Brannigan, J.A., Muchová, K., Barák, I. & Wilkinson, A.J. Phosphorylated aspartate in the structure of a response regulator protein. J. Mol. Biol. 294, 9–15 (1999).

    Article  CAS  Google Scholar 

  21. Cho, H.S. et al. NMR structure of activated CheY. J. Mol. Biol. 297, 543–551 (2000).

    Article  CAS  Google Scholar 

  22. Halkides, C.J. et al. The 1.9 Å resolution crystal structure of phosphono-CheY, an analogue of the active form of the response regulator, CheY. Biochemistry 39, 5280–5286 (2000).

    Article  CAS  Google Scholar 

  23. Stock, J.B., Stock, A.M. & Mottonen, J.M. Signal transduction in bacteria. Nature 344, 395–400 (1990).

    Article  CAS  Google Scholar 

  24. Wigley, D.B., Davies, G.J., Dodson, E.J., Maxwell, A. & Dodson, G. Crystal structure of an N-terminal fragment of the DNA gyrase B protein. Nature 351, 624–629 (1991).

    Article  CAS  Google Scholar 

  25. Prodromou, C. et al. Identification and structural characterization of the ATP/ADP-binding site in the Hsp90 molecular chaperone. Cell 90, 65–75 (1997).

    Article  CAS  Google Scholar 

  26. Ban, C. & Yang, W. Crystal structure and ATPase activity of MutL: implications for DNA repair and mutagenesis. Cell 95, 541–552 (1998).

    Article  CAS  Google Scholar 

  27. Mushegian, A.R., Bassett, D.E., Jr., Boguski, M.S., Bork, P. & Koonin, E.V. Positionally cloned human disease genes: patterns of evolutionary conservation and functional motifs. Proc. Natl. Acad. Sci. USA 94, 5831–5836 (1997).

    Article  CAS  Google Scholar 

  28. Ban, C., Junop, M. & Yang, W. Transformation of MutL by ATP binding and hydrolysis: a switch in DNA mismatch repair. Cell 97, 85–97 (1999).

    Article  CAS  Google Scholar 

  29. Brino, L. et al. Dimerization of Escherichia coli DNA-gyrase B provides a structural mechanism for activating the ATPase catalytic center. J. Biol. Chem. 275, 9468–9475 (2000).

    Article  CAS  Google Scholar 

  30. Yeh, K.-C., Wu, S.-H., Murphy, J.T. & Lagarias, J.C. A cyanobacterial phytochrome two-component light sensory system. Science 277, 1505–1508 (1997).

    Article  CAS  Google Scholar 

  31. Yeh, K.-C. & Lagarias, J.C. Eukaryotic phytochromes: light-regulated serine/threonine protein kinases with histidine kinase ancestry. Proc. Natl. Acad. Sci. USA 95, 13976–13981 (1998).

    Article  CAS  Google Scholar 

  32. Elich, T.D. & Chory, J. Phytochrome: If it looks and smells like a histidine-kinase, is it a histidine kinase? Cell 91, 713–716 (1997).

    Article  CAS  Google Scholar 

  33. Wu, J., Ohta, N., Zhao, J.L. & Newton, A. A novel bacterial tyrosine kinase essential for cell division and differentiation. Proc. Natl. Acad. Sci. USA 96, 13068–13073 (1999).

    Article  CAS  Google Scholar 

  34. Ryazanov, A.G., Pavur, K.S. & Dorovkov, M.V. Alpha-kinases: a new class of protein kinases with a novel catalytic domain. Curr. Biol. 9, R43–R45 (1999).

    Article  CAS  Google Scholar 

  35. Varughese, K.I., Madhusudan, Zhou, X.Z., Whiteley, J.M. & Hoch, J.A. Formation of a novel four-helix bundle and molecular recognition sites by dimerization of a response regulator phosphotransferase. Mol. Cell. 2, 485–493 (1998).

    Article  CAS  Google Scholar 

  36. Zhou, H., Lowry, D.F., Swanson, R.V., Simon, M.I. & Dahlquist, F.W. NMR studies of the phosphotransfer domain of the histidine kinase CheA from Escherichia coli: assignments, secondary structure, general fold, and backbone dynamics. Biochemistry 34, 13858–13870 (1995).

    Article  CAS  Google Scholar 

  37. Kato, M., Mizuno, T., Shimizu, T. & Hakoshima, T. Insights into multistep phosphorelay from the crystal structure of the C-terminal HPt domain of ArcB. Cell 88, 717–723 (1997).

    Article  CAS  Google Scholar 

  38. Xu, Q. & West, A.H. Conservation of structure and function among histidine-containing phosphotransfer (HPt) domains as revealed by the crystal structure of YPD1. J. Mol. Biol. 292, 1039–1050 (1999).

    Article  CAS  Google Scholar 

  39. Park, H. & Inouye, M. Mutational analysis of the linker region of EnvZ, an osmosensor in Escherichia coli. J. Bacteriol. 179, 4382–4390 (1997).

    Article  CAS  Google Scholar 

  40. Singh, M., Berger, B., Kim, P.S., Berger, J.M. & Cochran, A.G. Computational learning reveals coiled coil-like motifs in histidine kinase linker domains. Proc. Natl. Acad. Sci. USA 95, 2738–2743 (1998).

    Article  CAS  Google Scholar 

  41. Aravind, L. & Ponting, C.P. The cytoplasmic helical linker domain of receptor histidine kinase and methyl-accepting proteins is common to many prokaryotic signalling proteins. FEMS Microbiol. Lett. 176, 111–116 (1999).

    Article  CAS  Google Scholar 

  42. Taylor, B.L. & Zhulin, I.B. PAS domains: internal sensors of oxygen, redox potential, and light. Microbiol. Mol. Biol. Rev. 63, 479–506 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Gong, W. et al. Structure of a biological oxygen sensor: a new mechanism for heme-driven signal transduction. Proc. Natl. Acad. Sci. USA 95, 15177–15182 (1998).

    Article  CAS  Google Scholar 

  44. Pellequer, J.L., Wager-Smith, K.A., Kay, S.A. & Getzoff, E.D. Photoactive yellow protein: a structural prototype for the three-dimensional fold of the PAS domain superfamily. Proc. Natl. Acad. Sci. USA 95, 5884–5890 (1998).

    Article  CAS  Google Scholar 

  45. Aravind, L. & Ponting, C.P. The GAF domain: an evolutionary link between diverse phototransducing proteins. Trends Biochem. Sci. 22, 458–459 (1997).

    Article  CAS  Google Scholar 

  46. Artymiuk, P.J., Rice, D.W., Mitchell, E.M. & Willet, P. Structural resemblance between the families of bacterial signal-transducing proteins and of G proteins revealed by graph theoretical techniques. Protein Eng. 4, 39–43 (1990).

    Article  CAS  Google Scholar 

  47. Chen, J.M., Lee, G., Murphy, R.B., Brandt-Rauf, P.W. & Pincus, M.R. Comparisons between the three-dimensional structures of the chemotactic protein CheY and the normal Gly 12‐p21 protein. Int. J. Pept. Protein Res. 36, 1–6 (1990).

    Article  CAS  Google Scholar 

  48. Stock, J.B., Lukat, G.S. & Stock, A.M. Bacterial chemotaxis and the molecular logic of intracellular signal transduction networks. Annu. Rev. Biophys. Biophys. Chem. 20, 109–136 (1991).

    Article  CAS  Google Scholar 

  49. Jencks, W.P. The utilization of binding energy in coupled vectorial processes. Adv. Enzymol. 51, 75–106 (1980).

    CAS  PubMed  Google Scholar 

  50. Tanford, C. Twenty questions concerning the reaction cycle of the sarcoplasmic reticulum calcium pump. CRC Crit. Rev. Biochem. 17, 123–151 (1984).

    Article  CAS  Google Scholar 

  51. Volz, K. Structural conservation in the CheY superfamily. Biochemistry 32, 11741–11753 (1993).

    Article  CAS  Google Scholar 

  52. Stock, A.M., Mottonen, J.M., Stock, J.B. & Schutt, C.E. Three-dimensional structure of CheY, the response regulator of bacterial chemotaxis. Nature 337, 745–749 (1989).

    Article  CAS  Google Scholar 

  53. Djordjevic, S., Goudreau, P.N., Xu, Q., Stock, A.M. & West, A.H. Structural basis for methylesterase CheB regulation by a phosphorylation-activated domain. Proc. Natl. Acad. Sci. USA 95, 1381–1386 (1998).

    Article  CAS  Google Scholar 

  54. Muller-Dieckmann, H.J., Grantz, A.A. & Kim, S.H. The structure of the signal receiver domain of the Arabidopsis thaliana ethylene receptor ETR1. Structure Fold. Des. 7, 1547–1556 (1999).

    Article  CAS  Google Scholar 

  55. Gouet, P. et al. Structural transitions in the FixJ receiver domain. Structure 7, 1517–1526 (1999).

    Article  CAS  Google Scholar 

  56. Baikalov, I. et al. NarL dimerization? Suggestive evidence from a new crystal form. Biochemistry 37, 3665–3676 (1998).

    Article  CAS  Google Scholar 

  57. Volkman, B.F., Nohaile, M.J., Amy, N.K., Kustu, S. & Wemmer, D.E. Three-dimensional solution structure of the N-terminal receiver domain of NtrC. Biochemistry 34, 1413–1424 (1995).

    Article  CAS  Google Scholar 

  58. Solà, M., Gomis-Rüth, F.X., Serrano, L., González, A. & Coll, M. Three-dimensional crystal structure of the transcription factor PhoB receiver domain. J. Mol. Biol. 285, 675–687 (1999).

    Article  Google Scholar 

  59. Madhusudan et al. Crystal structure of a phosphatase-resistant mutant of sporulation response regulator Spo0F from Bacillus subtilis. Structure 4, 679–690 (1996).

    Article  CAS  Google Scholar 

  60. Lukat, G.S., McCleary, W.R., Stock, A.M. & Stock, J.B. Phosphorylation of bacterial response regulator proteins by low molecular weight phospho-donors. Proc. Natl. Acad. Sci. USA 89, 718–722 (1992).

    Article  CAS  Google Scholar 

  61. Lukat, G.S., Stock, A.M. & Stock, J.B. Divalent metal ion binding to the CheY protein and its significance to phosphotransfer in bacterial chemotaxis. Biochemistry 29, 5436–5442 (1990).

    Article  CAS  Google Scholar 

  62. Martinez-Hackert, E. & Stock, A.M. Structural relationships in the OmpR family of winged-helix transcription factors. J. Mol. Biol. 269, 301–312 (1997).

    Article  CAS  Google Scholar 

  63. Mizuno, T. & Tanaka, I. Structure of the DNA-binding domain of the OmpR family of response regulators. Mol. Microbiol. 24, 665–667 (1997).

    Article  CAS  Google Scholar 

  64. Osuna, J., Soberon, X. & Morett, E. A proposed architecture for the central domain of the bacterial enhancer-binding proteins based on secondary structure prediction and fold recognition. Protein Sci. 6, 543–555 (1997).

    Article  CAS  Google Scholar 

  65. Pelton, J.G., Kustu, S. & Wemmer, D.E. Solution structure of the DNA-binding domain of NtrC with three alanine substitutions. J. Mol. Biol. 292, 1095–1110 (1999).

    Article  CAS  Google Scholar 

  66. Zhu, X., Rebello, J., Matsumura, P. & Volz, K. Crystal structures of CheY mutants Y106W and T87I/Y106W: CheY activation correlates with movement of residue 106. J. Biol. Chem. 272, 5000–5006 (1997).

    Article  CAS  Google Scholar 

  67. Nohaile, M., Kern, D., Wemmer, D., Stedman, K. & Kustu, S. Structural and functional analyses of activating amino acid substitutions in the receiver domain of NtrC: evidence for an activating surface. J. Mol. Biol. 273, 299–316 (1997).

    Article  CAS  Google Scholar 

  68. Yan, D. et al. Beryllofluoride mimics phosphorylation of NtrC and other bacterial response regulators. Proc. Natl. Acad. Sci. USA 96, 14789–14794 (1999).

    Article  CAS  Google Scholar 

  69. Lewis, R.J. et al. Domain swapping in the sporulation response regulator Spo0A. J. Mol. Biol. 297, 757–770 (2000).

    Article  CAS  Google Scholar 

  70. Ames, S.K., Frankema, N. & Kenney, L.J. C-terminal DNA binding stimulates N-terminal phosphorylation of the outer membrane protein regulator OmpR from Escherichia coli. Proc. Natl. Acad. Sci. USA 96, 11792–11797 (1999).

    Article  CAS  Google Scholar 

  71. Hwang, I., Thorgeirsson, T., Lee, J., Kustu, S. & Shin, Y.K. Physical evidence for a phosphorylation-dependent conformational change in the enhancer-binding protein NtrC. Proc. Natl. Acad. Sci. USA 96, 4880–4885 (1999).

    Article  CAS  Google Scholar 

  72. Anand, G.A., Goudreau, P.N., Lewis, J.K. & Stock, A.M. Evidence for phosphorylation-dependent conformational changes in methylesterase CheB. Protein Sci. 9, 898–906 (2000).

    Article  CAS  Google Scholar 

  73. Welch, M., Chinardet, N., Mourey, L., Birck, C. & Samama, J.-P. Structure of the CheY-binding domain of histidine kinase CheA in complex with CheY. Nature Struct. Biol. 5, 25–29 (1998).

    Article  CAS  Google Scholar 

  74. McEvoy, M.M., Hausrath, A.C., Randolph, G.B., Remington, S.J. & Dahlquist, F.W. Two binding modes reveal flexibility in kinase/response regulator interactions in the bacterial chemotaxis pathway. Proc. Natl. Acad. Sci. USA 95, 7333–7338 (1998).

    Article  CAS  Google Scholar 

  75. McEvoy, M.M., Bren, A., Eisenbach, M. & Dahlquist, F.W. Identification of the binding interfaces on CheY for two of its targets, the phosphatase CheZ and the flagellar switch protein FliM. J. Mol. Biol. 289, 1423–1433 (1999).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank G. Anand, K. Gunsalus, J. Hurley and C. Waldburger for comments on the manuscript and/or for providing unpublished information, and the NIH and HHMI for support.

Author information

Authors and Affiliations

  1. Center for Advanced Biotechnology and Medicine and Department of Biochemistry, UMDNJ-Robert Wood Johnson Medical School, 679 Hoes Lane, Piscataway, 08854-5627, New Jersey, USA

    Victoria L. Robinson, David R. Buckler & Ann M. Stock

  2. Howard Hughes Medical Institute, UMDNJ-Robert Wood Johnson Medical School, 679 Hoes Lane, Piscataway, 08854-5627, New Jersey, USA

    Victoria L. Robinson & Ann M. Stock

Authors
  1. Victoria L. Robinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David R. Buckler
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ann M. Stock
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ann M. Stock.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Robinson, V., Buckler, D. & Stock, A. A tale of two components: a novel kinase and a regulatory switch. Nat Struct Mol Biol 7, 626–633 (2000). https://doi.org/10.1038/77915

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/77915

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing