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. 2000 Mar;9(3):610–618. doi: 10.1110/ps.9.3.610

Structural similarities and differences in Staphylococcus aureus exfoliative toxins A and B as revealed by their crystal structures.

A C Papageorgiou 1, L R Plano 1, C M Collins 1, K R Acharya 1
PMCID: PMC2144578  PMID: 10752623

Abstract

Staphylococcal aureus epidermolytic toxins (ETs) A and B are responsible for the induction of staphylococcal scalded skin syndrome, a disease of neonates and young children. The clinical features of this syndrome vary from localized blisters to severe exfoliation affecting most of the body surface. Comparison of the crystal structures of two subtypes of ETs-rETA (at 2.0 A resolution), rETB (at 2.8 A resolution), and an active site variant of rETA, Ser195Ala at 2.0 A resolution has demonstrated that their overall topology resembles that of a "trypsin-like" serine protease, but with significant differences at the N- and C-termini and loop regions. The details of the catalytic site in both ET structures are very similar to those in glutamate-specific serine proteases, suggesting a common catalytic mechanism. However, the "oxyanion hole," which is part of the catalytic sites of glutamate specific serine proteases, is in the closed or inactive conformation for rETA, yet in the open or active conformation for rETB. The ETs contain a unique amphipathic helix at the N-terminus, and it appears to be involved in optimizing the conformation of the catalytic site residues. Determination of the structure of the rETA catalytic site variant, Ser195Ala, showed no significant perturbation at the active site, establishing that the loss of biological and esterolytic activity can be attributed solely to disruption of the catalytic serine residue. Finally, the crystal structure of ETs, together with biochemical data and mutagenesis studies, strongly confirms the classification of these molecules as "serine proteases" rather than "superantigens."

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Selected References

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  1. Bailey C. J., Redpath M. B. The esterolytic activity of epidermolytic toxins. Biochem J. 1992 May 15;284(Pt 1):177–180. doi: 10.1042/bj2840177. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Brünger A. T., Adams P. D., Clore G. M., DeLano W. L., Gros P., Grosse-Kunstleve R. W., Jiang J. S., Kuszewski J., Nilges M., Pannu N. S. Crystallography & NMR system: A new software suite for macromolecular structure determination. Acta Crystallogr D Biol Crystallogr. 1998 Sep 1;54(Pt 5):905–921. doi: 10.1107/s0907444998003254. [DOI] [PubMed] [Google Scholar]
  3. Brünger A. T., Kuriyan J., Karplus M. Crystallographic R factor refinement by molecular dynamics. Science. 1987 Jan 23;235(4787):458–460. doi: 10.1126/science.235.4787.458. [DOI] [PubMed] [Google Scholar]
  4. Cavarelli J., Prévost G., Bourguet W., Moulinier L., Chevrier B., Delagoutte B., Bilwes A., Mourey L., Rifai S., Piémont Y. The structure of Staphylococcus aureus epidermolytic toxin A, an atypic serine protease, at 1.7 A resolution. Structure. 1997 Jun 15;5(6):813–824. doi: 10.1016/s0969-2126(97)00235-9. [DOI] [PubMed] [Google Scholar]
  5. Esnouf R. M. An extensively modified version of MolScript that includes greatly enhanced coloring capabilities. J Mol Graph Model. 1997 Apr;15(2):132-4, 112-3. doi: 10.1016/S1093-3263(97)00021-1. [DOI] [PubMed] [Google Scholar]
  6. Fleischer B., Bailey C. J. Recombinant epidermolytic (exfoliative) toxin A of Staphylococcus aureus is not a superantigen. Med Microbiol Immunol. 1992;180(6):273–278. doi: 10.1007/BF00191548. [DOI] [PubMed] [Google Scholar]
  7. Ho S. N., Hunt H. D., Horton R. M., Pullen J. K., Pease L. R. Site-directed mutagenesis by overlap extension using the polymerase chain reaction. Gene. 1989 Apr 15;77(1):51–59. doi: 10.1016/0378-1119(89)90358-2. [DOI] [PubMed] [Google Scholar]
  8. Jackson M. P., Iandolo J. J. Cloning and expression of the exfoliative toxin B gene from Staphylococcus aureus. J Bacteriol. 1986 May;166(2):574–580. doi: 10.1128/jb.166.2.574-580.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. 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. 1991 Mar 1;47(Pt 2):110–119. doi: 10.1107/s0108767390010224. [DOI] [PubMed] [Google Scholar]
  10. Kabsch W., Sander C. Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features. Biopolymers. 1983 Dec;22(12):2577–2637. doi: 10.1002/bip.360221211. [DOI] [PubMed] [Google Scholar]
  11. Kim J. L., Morgenstern K. A., Lin C., Fox T., Dwyer M. D., Landro J. A., Chambers S. P., Markland W., Lepre C. A., O'Malley E. T. Crystal structure of the hepatitis C virus NS3 protease domain complexed with a synthetic NS4A cofactor peptide. Cell. 1996 Oct 18;87(2):343–355. doi: 10.1016/s0092-8674(00)81351-3. [DOI] [PubMed] [Google Scholar]
  12. Ladhani S., Joannou C. L., Lochrie D. P., Evans R. W., Poston S. M. Clinical, microbial, and biochemical aspects of the exfoliative toxins causing staphylococcal scalded-skin syndrome. Clin Microbiol Rev. 1999 Apr;12(2):224–242. doi: 10.1128/cmr.12.2.224. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Monday S. R., Vath G. M., Ferens W. A., Deobald C., Rago J. V., Gahr P. J., Monie D. D., Iandolo J. J., Chapes S. K., Davis W. C. Unique superantigen activity of staphylococcal exfoliative toxins. J Immunol. 1999 Apr 15;162(8):4550–4559. [PubMed] [Google Scholar]
  14. Nienaber V. L., Breddam K., Birktoft J. J. A glutamic acid specific serine protease utilizes a novel histidine triad in substrate binding. Biochemistry. 1993 Nov 2;32(43):11469–11475. doi: 10.1021/bi00094a001. [DOI] [PubMed] [Google Scholar]
  15. Papageorgiou A. C., Acharya K. R. Superantigens as immunomodulators: recent structural insights. Structure. 1997 Aug 15;5(8):991–996. doi: 10.1016/s0969-2126(97)00252-9. [DOI] [PubMed] [Google Scholar]
  16. Perona J. J., Craik C. S. Structural basis of substrate specificity in the serine proteases. Protein Sci. 1995 Mar;4(3):337–360. doi: 10.1002/pro.5560040301. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Prévost G., Rifai S., Chaix M. L., Piémont Y. Functional evidence that the Ser-195 residue of staphylococcal exfoliative toxin A is essential for biological activity. Infect Immun. 1991 Sep;59(9):3337–3339. doi: 10.1128/iai.59.9.3337-3339.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Redpath M. B., Foster T. J., Bailey C. J. The role of the serine protease active site in the mode of action of epidermolytic toxin of Staphylococcus aureus. FEMS Microbiol Lett. 1991 Jun 15;65(2):151–155. doi: 10.1016/0378-1097(91)90295-l. [DOI] [PubMed] [Google Scholar]
  19. Sakurai S., Suzuki H., Saito S., Konishi Y., Machida K., Kohno M. New evidence that the Tyr-157 and Tyr-159 residues of staphylococcal exfoliative toxin B are essential for its toxicity. Microbiol Immunol. 1998;42(12):829–836. doi: 10.1111/j.1348-0421.1998.tb02358.x. [DOI] [PubMed] [Google Scholar]
  20. Schechter I., Berger A. On the size of the active site in proteases. I. Papain. Biochem Biophys Res Commun. 1967 Apr 20;27(2):157–162. doi: 10.1016/s0006-291x(67)80055-x. [DOI] [PubMed] [Google Scholar]
  21. Stennicke H. R., Birktoft J. J., Breddam K. Characterization of the S1 binding site of the glutamic acid-specific protease from Streptomyces griseus. Protein Sci. 1996 Nov;5(11):2266–2275. doi: 10.1002/pro.5560051113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Stuart D. I., Levine M., Muirhead H., Stammers D. K. Crystal structure of cat muscle pyruvate kinase at a resolution of 2.6 A. J Mol Biol. 1979 Oct 15;134(1):109–142. doi: 10.1016/0022-2836(79)90416-9. [DOI] [PubMed] [Google Scholar]
  23. Vath G. M., Earhart C. A., Monie D. D., Iandolo J. J., Schlievert P. M., Ohlendorf D. H. The crystal structure of exfoliative toxin B: a superantigen with enzymatic activity. Biochemistry. 1999 Aug 10;38(32):10239–10246. doi: 10.1021/bi990721e. [DOI] [PubMed] [Google Scholar]
  24. Vath G. M., Earhart C. A., Rago J. V., Kim M. H., Bohach G. A., Schlievert P. M., Ohlendorf D. H. The structure of the superantigen exfoliative toxin A suggests a novel regulation as a serine protease. Biochemistry. 1997 Feb 18;36(7):1559–1566. doi: 10.1021/bi962614f. [DOI] [PubMed] [Google Scholar]

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