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J. Biol. Chem., Vol. 281, Issue 15, 10439-10447, April 14, 2006

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Efficient Leukocyte Ig-like Receptor Signaling and Crystal Structure of Disulfide-linked HLA-G Dimer^*

Mitsunori Shiroishi¹, Kimiko Kuroki, Toyoyuki Ose, Linda Rasubala², Ikuo Shiratori^¶, Hisashi Arase^¶, Kouhei Tsumoto^||, Izumi Kumagai^||, Daisuke Kohda³, and Katsumi Maenaka³⁴

From the Division of Structural Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, the Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Yamadaoka 3-1, Suita, Osaka 565-0871, and ^¶PRESTO, Japan Science and Technology Agency, Saitama 332-0012, and the ^||Department of Biomolecular Engineering, Graduate School of Engineering, Tohoku University, Aoba-yama 07, Sendai 980-8579, Japan

HLA-G is a nonclassical major histocompatibility complex class I (MHCI) molecule, which is expressed in trophoblasts and confers immunological tolerance in the maternal-fetal interface by binding to leukocyte Ig-like receptors (LILRs, also called as LIR/ILT/CD85) and CD8. HLA-G is expressed in disulfide-linked dimer form both in solution and at the cell surface. Interestingly, MHCI dimer formations have been involved in pathogenesis and T cell activation. The structure and receptor binding characteristics of MHCI dimers have never been evaluated. Here we performed binding studies showing that the HLA-G dimer exhibited higher overall affinity to LILRB1/2 than the monomer by significant avidity effects. Furthermore, the cell reporter assay demonstrated that the dimer formation remarkably enhanced the LILRB1-mediated signaling at the cellular level. We further determined the crystal structure of the wild-type dimer of HLA-G with the intermolecular Cys⁴²-Cys⁴² disulfide bond. This dimer structure showed the oblique configuration to expose two LILR/CD8-binding sites upward from the membrane easily accessible for receptors, providing plausible 1:2 (HLA-G dimer:receptors) complex models. These results indicated that the HLA-G dimer conferred increased avidity in a proper structural orientation to induce efficient LILR signaling, resulting in the dominant immunosuppressive effects. Moreover, structural and functional implications for other MHCI dimers observed in activated T cells and the pathogenic allele, HLA-B27, are discussed.

Received for publication, November 16, 2005

The atomic coordinates and structure factors (code 2D31) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* 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 on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S1 and S2 and supplemental Figs. S1-S4.

¹ Supported in part by Sasakawa scientific research grant from the Japan Science Society and a Japan Society for the Promotion of Science postdoctoral fellowship.

² Supported by a Japan Society for the Promotion of Science postdoctoral fellowship for foreign researchers.

³ Supported in part by the Ministry of Education, Science, Sports, Culture and Technology of Japan and the Protein 3000 Project.

⁴ Supported in part by the Kanae Foundation. To whom correspondence should be addressed: Division of Structural Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan. Tel.: 81-92-642-6969; Fax: 81-92-642-6764; E-mail: kmaenaka{at}bioreg.kyushu-u.ac.jp.

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