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.

  • Article
  • Published:

Insights into pneumococcal pathogenesis from the crystal structure of the modular teichoic acid phosphorylcholine esterase Pce

Abstract

Phosphorylcholine, a specific component of the pneumococcal cell wall, is crucial in pathogenesis. It directly binds to the human platelet-activating factor (PAF) receptor and acts as a docking station for the family of surface-located choline-binding proteins (CBP). The first structure of a complete pneumococcal CBP, Pce (or CbpE), has been solved in complex with the reaction product and choline analogs. Pce has a novel modular structure, with a globular N-terminal module containing a binuclear Zn2+ catalytic center, and an elongated choline-binding module. Residues involved in substrate binding and catalysis are described and modular configuration of the active center accounts for in vivo features of teichoic acid hydrolysis. The hydrolysis of PAF by Pce and its regulatory role in phosphorylcholine decoration of the bacterial surface provide new insights into the critical function of Pce in pneumococcal adherence and invasiveness.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Structure of Pce in complex with PC and choline analogs.
Figure 2: Metal-binding sites in Pce.
Figure 3: Hydrolysis of PAF and n-dodecylphosphorylcholine by Pce.
Figure 4: Proposed model of interaction between Pce and pentameric teichoic acid chains.

Similar content being viewed by others

Accession codes

Accessions

BINDPlus

Protein Data Bank

References

  1. Swiatlo, E., McDaniel, L.S. & Briles, D.E. Choline-binding proteins. In The Pneumococcus (eds. Tuomanen, E.I., Mitchell, T.J., Morrison, D.A. & Spratt, B.G.) 49–60 (ASM Press, Washington, DC, 2004).

    Google Scholar 

  2. López, R., García, E., García, P. & García, J.L. Cell wall hydrolases. In The Pneumococcus (eds. Tuomanen, E.I., Mitchell, T.J., Morrison, D.A. & Spratt, B.G.) 75–88 (ASM Press, Washington, DC, 2004).

    Google Scholar 

  3. López, R., García, E., García, P., Ronda, C. & Tomasz, A. Choline-containing bacteriophage receptors in Streptococcus pneumoniae. J. Bacteriol. 151, 1581–1590 (1982).

    PubMed  PubMed Central  Google Scholar 

  4. Pepys, M.B. & Hirschfield, G.M. C-reactive protein: a critical update. J. Clin. Invest. 111, 1805–1812 (2003).

    Article  CAS  Google Scholar 

  5. Cundell, D.R., Gerard, N.P., Gerard, C., Idanpaan-Heikkila, I. & Tuomanen, E.I. Streptococcus pneumoniae anchors to activated human cells by the receptor for platelet-activating factor. Nature 377, 435–438 (1995).

    Article  CAS  Google Scholar 

  6. García, E. et al. Molecular evolution of lytic enzymes of Streptococcus pneumoniae and its bacteriophages. Proc. Natl. Acad. Sci. USA 85, 914–918 (1988).

    Article  Google Scholar 

  7. López, R. & García, E. Recent trends on the molecular biology of pneumococcal capsules, lytic enzymes, and bacteriophage. FEMS Microbiol. Rev 28, 553–580 (2004).

    Article  Google Scholar 

  8. Sánchez-Beato, A.R., López, R. & García, J.L. Molecular characterization of PcpA: a novel choline-binding protein of Streptococcus pneumoniae. FEMS Microbiol. Lett. 164, 207–214 (1998).

    Article  Google Scholar 

  9. Rosenow, C. et al. Contribution of novel choline-binding proteins to adherence, colonization and immunogenicity of Streptococcus pneumoniae. Mol. Microbiol. 25, 819–829 (1997).

    Article  CAS  Google Scholar 

  10. Crain, M.J. et al. Pneumococcal surface protein A (PspA) is serologically highly variable and is expressed by all clinically important capsular serotypes of Streptococcus pneumoniae. Infect. Immun. 58, 3293–3299 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Hammerschmidt, S., Talay, S.R., Brandtzaeg, P. & Chhatwal, G.S. SpsA, a novel pneumococcal surface protein with specific binding to secretory immunoglobulin A and secretory component. Mol. Microbiol. 25, 1113–1124 (1997).

    Article  CAS  Google Scholar 

  12. Brooks-Walter, A., Briles, D.E. & Hollingshead, S.K. The pspC gene of Streptococcus pneumoniae encodes a polymorphic protein, PspC, with elicits cross-reactive antibodies to PspA and provides immunity to pneumococcal bacteremia. Infect. Immun. 67, 6533–6542 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Tu, A.H., Fulgham, R.L., McCroy, M.A., Briles, D.E. & Szalai, A.J. Pneumococcal surface protein A inhibits complement activation by Streptococcus pneumoniae. Infect. Immun. 67, 4720–4724 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. De las Rivas, B., García, J.L., López, R. & García, P. Molecular characterization of the pneumococcal teichoic acid phosphorylcholine esterase. Microb. Drug Resist. 7, 213–222 (2001).

    Article  CAS  Google Scholar 

  15. Vollmer, W. & Tomasz, A. Identification of the teichoic acid phosphorylcholine esterase in Streptococcus pneumoniae. Mol. Microbiol. 39, 1610–1622 (2001).

    Article  CAS  Google Scholar 

  16. Höltje, J.V. & Tomasz, A. Teichoic acid phophorylcholine esterase. A novel enzyme activity in pneumococcus. J. Biol. Chem. 249, 7032–7034 (1974).

    PubMed  Google Scholar 

  17. Gosink, K.K., Mann, E.R., Guglielmo, C., Tuomanen, E.I. & Masure, H.R. Role of novel choline binding proteins in virulence of Streptococcus pneumoniae. Infect. Immun. 68, 5690–5695 (2000).

    Article  CAS  Google Scholar 

  18. Austrian, R. Some aspects of the pneumococcal carrier state. J. Antimicrob. Chemother. 18 suppl. A, 35–45 (1986).

    Article  Google Scholar 

  19. Fernández-Tornero, C., López, R., García, E., Giménez-Gallego, G. & Romero, A. A novel solenoid fold in the cell wall anchoring domain of the pneumococcal virulence factor LytA. Nat. Struct. Biol. 8, 1020–1024 (2001).

    Article  Google Scholar 

  20. Hermoso, J.A. et al. Structural basis for selective recognition of pneumococcal cell wall by modular endolysin from phage Cp-1. Structure 11, 1239–1249 (2003).

    Article  CAS  Google Scholar 

  21. Luo, R. et al. Solution structure of choline binding protein A, the major adhesin of Streptococcus pneumoniae. EMBO J. 24, 34–43 (2005).

    Article  CAS  Google Scholar 

  22. Holm, L. & Sander, C. Mapping the protein universe. Science 273, 595–603 (1996).

    Article  CAS  Google Scholar 

  23. Ullah, J.H. et al. The crystal structure of the L1 metallo-β-lactamase from Stenotrophomonas maltophilia at 1.7 Å resolution. J. Mol. Biol. 284, 125–136 (1998).

    Article  CAS  Google Scholar 

  24. Cameron, A.D., Ridderström, M., Olin, B. & Mannervik, B. Crystal structure of human glyoxalase II and its complex with a glutathione thiolester substrate analogue. Structure 7, 1067–1078 (1999).

    Article  CAS  Google Scholar 

  25. Frazao, C. et al. Structure of a dioxygen reduction enzyme from Desulfovibrio gigas. Nat. Struct. Biol. 7, 1041–1045 (2000).

    Article  CAS  Google Scholar 

  26. Rasia, R.M., Ceolín, M. & Vila, A.J. Grafting a new metal ligand in the cocatalytic site of B. cereus metallo-β-lactamase: Structural flexibility without loss of activity. Protein Sci. 12, 1538–1546 (2003).

    Article  CAS  Google Scholar 

  27. Hansen, S., Hansen, L.K. & Hough, E. Crystal structures of phosphate, iodide and iodate-inhibited phospholipase C from Bacillus cereus and structural investigations of the binding of reaction products and a substrate analogue. J. Mol. Biol. 225, 543–549 (1992).

    Article  CAS  Google Scholar 

  28. Hansen, S., Hough, E., Svensson, L.A., Wong, Y-L. & Martin, S.F. Crystal structure of phospholipase C from Bacillus cereus complexed with a substrate analog. J. Mol. Biol. 234, 179–187 (1993).

    Article  CAS  Google Scholar 

  29. Thompson, D., Pepys, M.B. & Wood, S.P. The physiological structure of human C-reactive protein and its complex with phosphocholine. Structure 7, 169–177 (1999).

    Article  CAS  Google Scholar 

  30. Dougherty, D.A. & Stauffer, D.A. Acetylcholine binding by a synthetic receptor: implications for biological recognition. Science 250, 1558–1560 (1990).

    Article  CAS  Google Scholar 

  31. Sanz, J.M., López, R. & García, J.L. Structural requirements of choline derivatives for “conversion” of pneumococcal amidase. FEBS Lett. 232, 308–312 (1988).

    Article  CAS  Google Scholar 

  32. Tomasz, A. Choline in the cell wall of a bacterium: novel type of polymer-linked choline in pneumococcus. Science 157, 694–697 (1967).

    Article  CAS  Google Scholar 

  33. Bean, B. & Tomasz, A. Choline metabolism in pneumococci. J. Bacteriol. 130, 571–574 (1977).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Behr, T., Fischer, W., Peter-Katalinic, J. & Edge, H. The structure of pneumococcal lipoteichoic acid. Improved preparation, chemical and mass spectrometric studies. Eur. J. Biochem. 207, 1063–1075 (1992).

    Article  CAS  Google Scholar 

  35. Tomasz, A. Biological consequences of the replacement of choline by ethanolamine in the cell wall of pneumococcus: chain formation, loss of transformability, and loss of autolysin. Proc. Natl. Acad. Sci. USA 59, 86–93 (1968).

    Article  CAS  Google Scholar 

  36. Yother, J., Handsome, G.L. & Briles, D.E. Truncated forms of PspA that are secreted from Streptococcus pneumoniae and their use in functional studies and cloning of the pspA gene. J. Bacteriol. 174, 610–618 (1992).

    Article  CAS  Google Scholar 

  37. Klein, R.A., Hartmann, R., Egge, H., Behr, T. & Fischer, W. The aqueous solution structure of a lipoteichoic acid from Streptococcus pneumoniae strain R6 containing 2,4-diamino-2,4,6-trideoxy-galactose: evidence for conformational mobility of the galactopyranose ring. Carbohydr. Res. 281, 79–98 (1996).

    Article  CAS  Google Scholar 

  38. Wilcox, D.E. Binuclear metallohydrolases. Chem. Rev. 96, 2435–2458 (1996).

    Article  CAS  Google Scholar 

  39. Lipscomb, W.N. & Sträter, N. Recent advances in zinc enzymology. Chem. Rev. 96, 2375–2434 (1996).

    Article  CAS  Google Scholar 

  40. Knowles, J.R. Enzyme-catalyzed phosphoryl transfer reactions. Annu. Rev. Biochem. 49, 877–919 (1980).

    Article  CAS  Google Scholar 

  41. O´Flaherty. J.T. & Wykle, R.L. In Platelet Activating Factor and Human Disease (eds. Barnes, P.J., Page, C.P. & Henson, P.) 117–137 (Blackwell Scientific, Oxford, 1989).

    Google Scholar 

  42. Lagartera, L. et al. Crystallization and preliminary X-ray diffraction studies of the pneumococcal teichoic acid phosphorylcholine esterase Pce. Acta Crystallogr. F 61, 221–224 (2005).

    Article  CAS  Google Scholar 

  43. Leslie, A.G.W. Profile fitting. In Proceedings of the CCP4 Study Weekend (eds. Machin, J.R. & Papiz, M.Z.) 39–50 (SERC Daresbury Laboratory, Warrington, UK, 1987).

    Google Scholar 

  44. Collaborative Computational Project, Number 4. The CCP4 suite: programs for protein crystallography. Acta Crystallogr. D 50, 760–763 (1994).

  45. Sheldrick, G.M. Direct Methods for Solving Macromolecular Structures 401–411 (Kluwer Academic, Dordrecht, The Netherlands, 1998).

    Book  Google Scholar 

  46. De la Fortelle, E. & Bricogne, G. Maximum-likelihood heavy atom parameter refinement in the MIR and MAD methods. Methods Enzymol. 276, 472–494 (1997).

    Article  CAS  Google Scholar 

  47. Jones, T.A., Zou, J.Y., Cowan, S.W. & Kjeldgaard, M. Improved methods for building protein models in electron density maps and the location of errors in these models. Acta Crystallogr. A 47, 110–119 (1991).

    Article  Google Scholar 

  48. Brunger, A.T. et al. Crystallography & NMR system: A new software suite for macromolecular structure determination. Acta Crystallogr. D 54, 905–921 (1998).

    Article  CAS  Google Scholar 

  49. Murshudov, G.N. Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallogr. D 53, 240–255 (1997).

    Article  CAS  Google Scholar 

  50. Laskowski, R.A., MacArthur, M.W., Moss, D.S. & Thornton, J.M. PROCHECK: a program to check the stereochemical quality of protein structures. J. Appl. Crystallogr. 26, 283–291 (1993).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank L. Serre for helpful suggestions, R. Kahn for help in data processing and analysis, Bracco Imaging (Milan) for providing a sample of Gd–HPDO3A, the staff of the BM30A beamline at the European Synchrotron Radiation Facility (Grenoble) for support and R.A. Klein for providing the atomic coordinates of the pentameric lipoteichoic acid. We thank R. López and E. García for critically reading the manuscript, W. Ran for correcting the English version and A. Torrecillas and SUIC staff for help in the ICP-OE measures. This work was supported by grants BIO2000-1307, BIO2002-02887, BIO2003-01952 and BMC2003-00074 from Dirección General de Investigación and by grant Contrato-Programa de Grupos Estratégicos (BMC2000-1002) de la Comunidad Autónoma de Madrid. L.L. and A.G. hold a fellowship from the Spanish Ministry of Science and Technology.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Juan A Hermoso.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Primary and secondary structures of crystallized teichoic acid phosphorylcholine esterase (Pce). (PDF 624 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hermoso, J., Lagartera, L., González, A. et al. Insights into pneumococcal pathogenesis from the crystal structure of the modular teichoic acid phosphorylcholine esterase Pce. Nat Struct Mol Biol 12, 533–538 (2005). https://doi.org/10.1038/nsmb940

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nsmb940

This article is cited by

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