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J. Biol. Chem., Vol. 282, Issue 9, 5991-6000, March 2, 2007

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Zinc Induces Dimerization of the Class II Major Histocompatibility Complex Molecule That Leads to Cooperative Binding to a Superantigen^*

Hongmin Li¹, Yiwei Zhao², Yi Guo, Zhong Li, Leslie Eisele, and Walid Mourad^¶

From the Wadsworth Center, New York State Department of Health, the Department of Biomedical Sciences, School of Public Health, University at Albany, State University of New York, Albany, New York 12208, and ^¶Université de Montréal, Centre Hospitalier de l'Université de Montréal, Campus St-Luc, Pavillon Edouard Asselin, 264, Boulevard RenéLévesque Est, Bureau 313, Montréal, Québec H2X 1P1, Canada

Dimerization of class II major histocompatibility complex (MHC) plays an important role in the MHC biological function. Mycoplasma arthritidis-derived mitogen (MAM) is a superantigen that can activate large fractions of T cells bearing specific T cell receptor V elements. Here we have used structural, sedimentation, and surface plasmon resonance detection approaches to investigate the molecular interactions between MAM and the class II MHC molecule HLA-DR1 in the context of a hemagglutinin peptide-(306–318) (HA). Our results revealed that zinc ion can efficiently induce the dimerization of the HLA-DR1/HA complex. Because the crystal structure of the MAM/HLA-DR1/hemagglutinin complex in the presence of EDTA is nearly identical to the structure of the complex crystallized in the presence of zinc ion, Zn²⁺ is evidently not directly involved in the binding between MAM and HLA-DR1. Sedimentation and surface plasmon resonance studies further revealed that MAM binds the HLA-DR1/HA complex with high affinity in a 1:1 stoichiometry, in the absence of Zn²⁺. However, in the presence of Zn²⁺, a dimerized MAM/HLA-DR1/HA complex can arise through the Zn²⁺-induced DR1 dimer. In the presence of Zn²⁺, cooperative binding of MAM to the DR1 dimer was also observed.

Received for publication, September 5, 2006 , and in revised form, December 5, 2006.

^* This work was supported by Grants AI50628 and AI64637 from the National Institutes of Health (to H. L.). 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.

The atomic coordinates and structure factors (code 2OJE) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

² Present address: ImmunoGen Inc., 128 Sidney St., Cambridge, MA 02139.

¹ To whom correspondence should be addressed: Wadsworth Center, New York State Department of Health, 120 New Scotland Ave., Albany, NY 12208. Tel.: 518-486-9154; Fax: 518-474-7992; E-mail: lih{at}wadsworth.org.

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