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 journalArticlepeer-review

151 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

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Efficient leukocyte Ig-like receptor signaling and crystal structure of disulfide-linked HLA-G dimer'. Together they form a unique fingerprint.

Cite this