Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1995 Sep 1;182(3):711–720. doi: 10.1084/jem.182.3.711

Staphylococcal enterotoxin A has two cooperative binding sites on major histocompatibility complex class II

PMCID: PMC2192176  PMID: 7650479

Abstract

The superantigen staphylococcal enterotoxin A (SEA) binds to major histocompatibility complex (MHC) class II molecules at two sites on either side of the peptide groove. Two separate but cooperative interactions to the human class II molecule HLA-DR1 were detected. The first high affinity interaction to the DR1 beta chain is mediated by a zinc atom coordinated by H187, H225, and D227 in SEA and H81 in the polymorphic DR1 beta chain. The second low affinity site is to the DR1 alpha chain analogous to SEB binding and is mediated by residue F47 in SEA. Binding of one SEA to the DR1 beta chain enhances the binding of a second SEA molecule to the DR1 alpha chain. The zinc site is on the opposite side of the SEA molecule from residue F47 so that one SEA molecule can readily bind two class II molecules. Both binding sites on SEA are required for maximal activity. Thus, unlike, SEB, SEA requires two separate binding sites for optimal activity, which may allow it to stabilize SEA interaction with T cell receptors, as well as to activate the antigen-presenting cell by cross-linking MHC class II.

Full Text

The Full Text of this article is available as a PDF (1.4 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Brown J. H., Jardetzky T. S., Gorga J. C., Stern L. J., Urban R. G., Strominger J. L., Wiley D. C. Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1. Nature. 1993 Jul 1;364(6432):33–39. doi: 10.1038/364033a0. [DOI] [PubMed] [Google Scholar]
  2. Chintagumpala M. M., Mollick J. A., Rich R. R. Staphylococcal toxins bind to different sites on HLA-DR. J Immunol. 1991 Dec 1;147(11):3876–3881. [PubMed] [Google Scholar]
  3. Choi Y. W., Kotzin B., Herron L., Callahan J., Marrack P., Kappler J. Interaction of Staphylococcus aureus toxin "superantigens" with human T cells. Proc Natl Acad Sci U S A. 1989 Nov;86(22):8941–8945. doi: 10.1073/pnas.86.22.8941. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  5. Cunningham B. C., Bass S., Fuh G., Wells J. A. Zinc mediation of the binding of human growth hormone to the human prolactin receptor. Science. 1990 Dec 21;250(4988):1709–1712. doi: 10.1126/science.2270485. [DOI] [PubMed] [Google Scholar]
  6. Cunningham B. C., Mulkerrin M. G., Wells J. A. Dimerization of human growth hormone by zinc. Science. 1991 Aug 2;253(5019):545–548. doi: 10.1126/science.1907025. [DOI] [PubMed] [Google Scholar]
  7. Dellabona P., Peccoud J., Kappler J., Marrack P., Benoist C., Mathis D. Superantigens interact with MHC class II molecules outside of the antigen groove. Cell. 1990 Sep 21;62(6):1115–1121. doi: 10.1016/0092-8674(90)90388-u. [DOI] [PubMed] [Google Scholar]
  8. Fischer H., Dohlsten M., Lindvall M., Sjögren H. O., Carlsson R. Binding of staphylococcal enterotoxin A to HLA-DR on B cell lines. J Immunol. 1989 May 1;142(9):3151–3157. [PubMed] [Google Scholar]
  9. Frankel A. D., Bredt D. S., Pabo C. O. Tat protein from human immunodeficiency virus forms a metal-linked dimer. Science. 1988 Apr 1;240(4848):70–73. doi: 10.1126/science.2832944. [DOI] [PubMed] [Google Scholar]
  10. Fraser J. D. High-affinity binding of staphylococcal enterotoxins A and B to HLA-DR. Nature. 1989 May 18;339(6221):221–223. doi: 10.1038/339221a0. [DOI] [PubMed] [Google Scholar]
  11. Fraser J. D., Urban R. G., Strominger J. L., Robinson H. Zinc regulates the function of two superantigens. Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5507–5511. doi: 10.1073/pnas.89.12.5507. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Glusker J. P. Structural aspects of metal liganding to functional groups in proteins. Adv Protein Chem. 1991;42:1–76. doi: 10.1016/s0065-3233(08)60534-3. [DOI] [PubMed] [Google Scholar]
  13. Gorga J. C., Horejsí V., Johnson D. R., Raghupathy R., Strominger J. L. Purification and characterization of class II histocompatibility antigens from a homozygous human B cell line. J Biol Chem. 1987 Nov 25;262(33):16087–16094. [PubMed] [Google Scholar]
  14. Griggs N. D., Pontzer C. H., Jarpe M. A., Johnson H. M. Mapping of multiple binding domains of the superantigen staphylococcal enterotoxin A for HLA. J Immunol. 1992 Apr 15;148(8):2516–2521. [PubMed] [Google Scholar]
  15. Hedlund G., Dohlsten M., Herrmann T., Buell G., Lando P. A., Segrén S., Schrimsher J., MacDonald H. R., Sjögren H. O., Kalland T. A recombinant C-terminal fragment of staphylococcal enterotoxin A binds to human MHC class II products but does not activate T cells. J Immunol. 1991 Dec 15;147(12):4082–4085. [PubMed] [Google Scholar]
  16. Herman A., Croteau G., Sekaly R. P., Kappler J., Marrack P. HLA-DR alleles differ in their ability to present staphylococcal enterotoxins to T cells. J Exp Med. 1990 Sep 1;172(3):709–717. doi: 10.1084/jem.172.3.709. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Herman A., Kappler J. W., Marrack P., Pullen A. M. Superantigens: mechanism of T-cell stimulation and role in immune responses. Annu Rev Immunol. 1991;9:745–772. doi: 10.1146/annurev.iy.09.040191.003525. [DOI] [PubMed] [Google Scholar]
  18. Herman A., Labrecque N., Thibodeau J., Marrack P., Kappler J. W., Sekaly R. P. Identification of the staphylococcal enterotoxin A superantigen binding site in the beta 1 domain of the human histocompatibility antigen HLA-DR. Proc Natl Acad Sci U S A. 1991 Nov 15;88(22):9954–9958. doi: 10.1073/pnas.88.22.9954. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Herrmann T., Accolla R. S., MacDonald H. R. Different staphylococcal enterotoxins bind preferentially to distinct major histocompatibility complex class II isotypes. Eur J Immunol. 1989 Nov;19(11):2171–2174. doi: 10.1002/eji.1830191131. [DOI] [PubMed] [Google Scholar]
  20. Hill C. P., Dauter Z., Dodson E. J., Dodson G. G., Dunn M. F. X-ray structure of an unusual Ca2+ site and the roles of Zn2+ and Ca2+ in the assembly, stability, and storage of the insulin hexamer. Biochemistry. 1991 Jan 29;30(4):917–924. doi: 10.1021/bi00218a006. [DOI] [PubMed] [Google Scholar]
  21. 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]
  22. Hudson K. R., Robinson H., Fraser J. D. Two adjacent residues in staphylococcal enterotoxins A and E determine T cell receptor V beta specificity. J Exp Med. 1993 Jan 1;177(1):175–184. doi: 10.1084/jem.177.1.175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Irwin M. J., Hudson K. R., Fraser J. D., Gascoigne N. R. Enterotoxin residues determining T-cell receptor V beta binding specificity. Nature. 1992 Oct 29;359(6398):841–843. doi: 10.1038/359841a0. [DOI] [PubMed] [Google Scholar]
  24. Jardetzky T. S., Brown J. H., Gorga J. C., Stern L. J., Urban R. G., Chi Y. I., Stauffacher C., Strominger J. L., Wiley D. C. Three-dimensional structure of a human class II histocompatibility molecule complexed with superantigen. Nature. 1994 Apr 21;368(6473):711–718. doi: 10.1038/368711a0. [DOI] [PubMed] [Google Scholar]
  25. Jorgensen J. L., Esser U., Fazekas de St Groth B., Reay P. A., Davis M. M. Mapping T-cell receptor-peptide contacts by variant peptide immunization of single-chain transgenics. Nature. 1992 Jan 16;355(6357):224–230. doi: 10.1038/355224a0. [DOI] [PubMed] [Google Scholar]
  26. Jorgensen J. L., Reay P. A., Ehrich E. W., Davis M. M. Molecular components of T-cell recognition. Annu Rev Immunol. 1992;10:835–873. doi: 10.1146/annurev.iy.10.040192.004155. [DOI] [PubMed] [Google Scholar]
  27. Kappler J. W., Herman A., Clements J., Marrack P. Mutations defining functional regions of the superantigen staphylococcal enterotoxin B. J Exp Med. 1992 Feb 1;175(2):387–396. doi: 10.1084/jem.175.2.387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Kappler J., Kotzin B., Herron L., Gelfand E. W., Bigler R. D., Boylston A., Carrel S., Posnett D. N., Choi Y., Marrack P. V beta-specific stimulation of human T cells by staphylococcal toxins. Science. 1989 May 19;244(4906):811–813. doi: 10.1126/science.2524876. [DOI] [PubMed] [Google Scholar]
  29. Karp D. R., Long E. O. Identification of HLA-DR1 beta chain residues critical for binding staphylococcal enterotoxins A and E. J Exp Med. 1992 Feb 1;175(2):415–424. doi: 10.1084/jem.175.2.415. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Lowman H. B., Cunningham B. C., Wells J. A. Mutational analysis and protein engineering of receptor-binding determinants in human placental lactogen. J Biol Chem. 1991 Jun 15;266(17):10982–10988. [PubMed] [Google Scholar]
  31. Marrack P., Blackman M., Kushnir E., Kappler J. The toxicity of staphylococcal enterotoxin B in mice is mediated by T cells. J Exp Med. 1990 Feb 1;171(2):455–464. doi: 10.1084/jem.171.2.455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Marrack P., Kappler J. The staphylococcal enterotoxins and their relatives. Science. 1990 May 11;248(4956):705–711. doi: 10.1126/science.2185544. [DOI] [PubMed] [Google Scholar]
  33. Mollick J. A., McMasters R. L., Grossman D., Rich R. R. Localization of a site on bacterial superantigens that determines T cell receptor beta chain specificity. J Exp Med. 1993 Feb 1;177(2):283–293. doi: 10.1084/jem.177.2.283. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Nabavi N., Freeman G. J., Gault A., Godfrey D., Nadler L. M., Glimcher L. H. Signalling through the MHC class II cytoplasmic domain is required for antigen presentation and induces B7 expression. Nature. 1992 Nov 19;360(6401):266–268. doi: 10.1038/360266a0. [DOI] [PubMed] [Google Scholar]
  35. Pullen A. M., Wade T., Marrack P., Kappler J. W. Identification of the region of T cell receptor beta chain that interacts with the self-superantigen MIs-1a. Cell. 1990 Jun 29;61(7):1365–1374. doi: 10.1016/0092-8674(90)90700-o. [DOI] [PubMed] [Google Scholar]
  36. Roberts V. A., Iverson B. L., Iverson S. A., Benkovic S. J., Lerner R. A., Getzoff E. D., Tainer J. A. Antibody remodeling: a general solution to the design of a metal-coordination site in an antibody binding pocket. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6654–6658. doi: 10.1073/pnas.87.17.6654. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Smith D. B., Johnson K. S. Single-step purification of polypeptides expressed in Escherichia coli as fusions with glutathione S-transferase. Gene. 1988 Jul 15;67(1):31–40. doi: 10.1016/0378-1119(88)90005-4. [DOI] [PubMed] [Google Scholar]
  38. Spertini F., Spits H., Geha R. S. Staphylococcal exotoxins deliver activation signals to human T-cell clones via major histocompatibility complex class II molecules. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7533–7537. doi: 10.1073/pnas.88.17.7533. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Swaminathan S., Furey W., Pletcher J., Sax M. Crystal structure of staphylococcal enterotoxin B, a superantigen. Nature. 1992 Oct 29;359(6398):801–806. doi: 10.1038/359801a0. [DOI] [PubMed] [Google Scholar]
  40. Vallee B. L., Auld D. S. Active-site zinc ligands and activated H2O of zinc enzymes. Proc Natl Acad Sci U S A. 1990 Jan;87(1):220–224. doi: 10.1073/pnas.87.1.220. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Vallee B. L., Auld D. S. Zinc coordination, function, and structure of zinc enzymes and other proteins. Biochemistry. 1990 Jun 19;29(24):5647–5659. doi: 10.1021/bi00476a001. [DOI] [PubMed] [Google Scholar]
  42. White J., Herman A., Pullen A. M., Kubo R., Kappler J. W., Marrack P. The V beta-specific superantigen staphylococcal enterotoxin B: stimulation of mature T cells and clonal deletion in neonatal mice. Cell. 1989 Jan 13;56(1):27–35. doi: 10.1016/0092-8674(89)90980-x. [DOI] [PubMed] [Google Scholar]
  43. White J., Pullen A., Choi K., Marrack P., Kappler J. W. Antigen recognition properties of mutant V beta 3+ T cell receptors are consistent with an immunoglobulin-like structure for the receptor. J Exp Med. 1993 Jan 1;177(1):119–125. doi: 10.1084/jem.177.1.119. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES