Crystal structure of HLA-G: a nonclassical MHC class I molecule expressed at the fetal-maternal interface

Proc Natl Acad Sci U S A. 2005 Mar 1;102(9):3360-5. doi: 10.1073/pnas.0409676102. Epub 2005 Feb 17.

Abstract

HLA-G is a nonclassical major histocompatibility complex class I (MHC-I) molecule that is primarily expressed at the fetal-maternal interface, where it is thought to play a role in protecting the fetus from the maternal immune response. HLA-G binds a limited repertoire of peptides and interacts with the inhibitory leukocyte Ig-like receptors LIR-1 and LIR-2 and possibly with certain natural killer cell receptors. To gain further insights into HLA-G function, we determined the 1.9-A structure of a monomeric HLA-G complexed to a natural endogenous peptide ligand from histone H2A (RIIPRHLQL). An extensive network of contacts between the peptide and the antigen-binding cleft reveal a constrained mode of binding reminiscent of the nonclassical HLA-E molecule, thereby providing a structural basis for the limited peptide repertoire of HLA-G. The alpha3 domain of HLA-G, a candidate binding site for the LIR-1 and -2 inhibitory receptors, is structurally distinct from the alpha3 domains of classical MHC-I molecules, providing a rationale for the observed affinity differences for these ligands. The structural data suggest a head-to-tail mode of dimerization, mediated by an intermolecular disulfide bond, that is consistent with the observation of HLA-G dimers on the cell surface.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Crystallography, X-Ray
  • Female
  • HLA Antigens / chemistry*
  • HLA Antigens / immunology
  • HLA-G Antigens
  • Histocompatibility Antigens Class I / chemistry*
  • Histocompatibility Antigens Class I / immunology
  • Humans
  • Maternal-Fetal Exchange / immunology*
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Pregnancy
  • Protein Conformation
  • Sequence Homology, Amino Acid

Substances

  • HLA Antigens
  • HLA-G Antigens
  • Histocompatibility Antigens Class I

Associated data

  • PDB/1YDP