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J. Biol. Chem., Vol. 279, Issue 2, 1297-1303, January 9, 2004

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Identification of a Secondary Zinc-binding Site in Staphylococcal Enterotoxin C2

IMPLICATIONS FOR SUPERANTIGEN RECOGNITION^*

Anastassios C. Papageorgiou, Matthew D. Baker, Julie D. McLeod¶||, Sayed K. Goda**, Claire N. Manzotti¶, David M. Sansom¶, Howard S. Tranter**, and K. Ravi Acharya¶¶

From the Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, the ^**Health Protection Agency, Centre for Applied Microbiology Research, Porton Down, Salisbury SP4 0JG, and the ^¶Division of Immunity and Infection, University of Birmingham Medical School, Birmingham B15 2TT, United Kingdom

The previously determined crystal structure of the superantigen staphylococcal enterotoxin C2 (SEC2) showed binding of a single zinc ion located between the N- and C-terminal domains (Papageorgiou, A. C., Acharya, K. R., Shapiro, R., Passalacqua, E. F., Brehm, R. D., and Tranter, H. S. (1995) Structure 3, 769-779). Here we present the crystal structure of SEC2 determined to 2.0 Å resolution in the presence of additional zinc. The structure revealed the presence of a secondary zinc-binding site close to the major histocompatibility complex (MHC)-binding site of the toxin and some 28 Å away from the primary zinc-binding site of the toxin found in previous studies. T cell stimulation assays showed that varying the concentration of zinc ions present affected the activity of the toxin and we observed that high zinc concentrations considerably inhibited T cell responses. This indicates that SEC2 may have multiple modes of interaction with the immune system that are dependent on serum zinc levels. The potential role of the secondary zinc-binding site and that of the primary one in the formation of the TCR·SEC2·MHC complex are considered, and the possibility that zinc may regulate the activity of SEC2 as a toxin facilitating different T cell responses is discussed.

Received for publication, July 9, 2003 , and in revised form, October 13, 2003.

The atomic coordinates and structure factors (code 1UNS) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by Programme Grant 9540039 (to K. R. A.) and Post-graduate Studentship G78/6152 (to M. D. B.) from the Medical Research Council (UK). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Current address: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, BioCity, Turku 20521, Finland.

^|| Current address: School of Biological Sciences, University of the West of England, Bristol BS16 1QY, Untied Kingdom.

Current address: Biochemistry/Genetic, Engineering Group, Faculty of Science, Cairo University, Giza, Egypt.

^¶¶ To whom correspondence should be addressed. Tel.: 44-1225-386238; Fax: 44-1225-386779; E-mail: K.R.Acharya{at}bath.ac.uk.

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