Efficient leukocyte Ig-like receptor signaling and crystal structure of disulfide-linked HLA-G dimer

Mitsunori Shiroishi, Kimiko Kuroki, Toyoyuki Ose, Linda Rasubala, Ikuo Shiratori, Hisashi Arase, Kouhei Tsumoto, Izumi Kumagai, Daisuke Kohda, Katsumi Maenaka

Research output: Contribution to journalArticle

140 Citations (Scopus)

Abstract

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-Cys 42 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.

Original languageEnglish
Pages (from-to)10439-10447
Number of pages9
JournalJournal of Biological Chemistry
Volume281
Issue number15
DOIs
Publication statusPublished - Apr 14 2006

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HLA-G Antigens
Disulfides
Dimers
Leukocytes
Crystal structure
Major Histocompatibility Complex
T-cells
T-Lymphocytes
HLA-B27 Antigen
Trophoblasts
Immunosuppressive Agents
Alleles
Binding Sites
Mothers
Membranes
Assays
Monomers
Chemical activation

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Shiroishi, M., Kuroki, K., Ose, T., Rasubala, L., Shiratori, I., Arase, H., ... Maenaka, K. (2006). Efficient leukocyte Ig-like receptor signaling and crystal structure of disulfide-linked HLA-G dimer. Journal of Biological Chemistry, 281(15), 10439-10447. https://doi.org/10.1074/jbc.M512305200

Efficient leukocyte Ig-like receptor signaling and crystal structure of disulfide-linked HLA-G dimer. / Shiroishi, Mitsunori; Kuroki, Kimiko; Ose, Toyoyuki; Rasubala, Linda; Shiratori, Ikuo; Arase, Hisashi; Tsumoto, Kouhei; Kumagai, Izumi; Kohda, Daisuke; Maenaka, Katsumi.

In: Journal of Biological Chemistry, Vol. 281, No. 15, 14.04.2006, p. 10439-10447.

Research output: Contribution to journalArticle

Shiroishi, M, Kuroki, K, Ose, T, Rasubala, L, Shiratori, I, Arase, H, Tsumoto, K, Kumagai, I, Kohda, D & Maenaka, K 2006, 'Efficient leukocyte Ig-like receptor signaling and crystal structure of disulfide-linked HLA-G dimer', Journal of Biological Chemistry, vol. 281, no. 15, pp. 10439-10447. https://doi.org/10.1074/jbc.M512305200
Shiroishi, Mitsunori ; Kuroki, Kimiko ; Ose, Toyoyuki ; Rasubala, Linda ; Shiratori, Ikuo ; Arase, Hisashi ; Tsumoto, Kouhei ; Kumagai, Izumi ; Kohda, Daisuke ; Maenaka, Katsumi. / Efficient leukocyte Ig-like receptor signaling and crystal structure of disulfide-linked HLA-G dimer. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 15. pp. 10439-10447.
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