title: Crystal structure of HLA-G: a nonclassical MHC class I molecule expressed at the fetal-maternal interface.
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.
authors.affiliation: Protein Crystallography Unit, Monash Centre for Synchrotron Science, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Craig S
authors.initials: CS
authors.lastname: Clements
authors.forename: Lars
authors.initials: L
authors.lastname: Kjer-Nielsen
authors.forename: Lyudmila
authors.initials: L
authors.lastname: Kostenko
authors.forename: Hilary L
authors.initials: HL
authors.lastname: Hoare
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Dunstone
authors.forename: Eric
authors.initials: E
authors.lastname: Moses
authors.forename: Katy
authors.initials: K
authors.lastname: Freed
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Brooks
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
authors.forename: James
authors.initials: J
authors.lastname: McCluskey
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D005260:Female; D006680:HLA Antigens / Q000737:chemistry* / Q000276:immunology; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000737:chemistry* / Q000276:immunology; D006801:Humans; D008431:Maternal-Fetal Exchange / Q000276:immunology*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011247:Pregnancy; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid
chemical_list: D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I
references.citation: J Immunol. 1998 Apr 1;160(7):3096-100
references.pmid: 9531263
references.citation: Annu Rev Immunol. 1993;11:213-44
references.pmid: 8476560
references.citation: Annu Rev Immunol. 1994;12:839-80
references.pmid: 8011299
references.citation: Annu Rev Immunol. 1995;13:587-622
references.pmid: 7612235
references.citation: Immunity. 1995 Nov;3(5):591-600
references.pmid: 7584149
references.citation: Curr Biol. 1996 Mar 1;6(3):305-14
references.pmid: 8805247
references.citation: Science. 1996 Dec 20;274(5295):2097-100
references.pmid: 8953044
references.citation: J Exp Med. 1997 Feb 3;185(3):385-91
references.pmid: 9053439
references.citation: J Immunol. 1997 Apr 15;158(8):3587-92
references.pmid: 9103419
references.citation: Nature. 1998 Feb 19;391(6669):795-9
references.pmid: 9486650
references.citation: Immunol Rev. 1999 Feb;167:233-44
references.pmid: 10319265
references.citation: J Exp Med. 1998 Mar 2;187(5):813-8
references.pmid: 9480992
references.citation: Immunity. 1999 Nov;11(5):603-13
references.pmid: 10591185
references.citation: J Biol Chem. 2000 May 19;275(20):15232-8
references.pmid: 10809759
references.citation: J Immunol. 2000 Jun 15;164(12):6398-405
references.pmid: 10843695
references.citation: Hum Immunol. 2000 Nov;61(11):1113-7
references.pmid: 11137215
references.citation: Acta Crystallogr D Biol Crystallogr. 2001 Oct;57(Pt 10):1367-72
references.pmid: 11567147
references.citation: Trends Immunol. 2001 Oct;22(10):548-52
references.pmid: 11574277
references.citation: Structure. 2001 Dec;9(12):1213-24
references.pmid: 11738047
references.citation: J Immunol Methods. 2002 Oct 1;268(1):43-50
references.pmid: 12213342
references.citation: J Immunol. 2002 Nov 1;169(9):5153-60
references.pmid: 12391232
references.citation: Acta Crystallogr D Biol Crystallogr. 2002 Dec;58(Pt 12):2131-4
references.pmid: 12454477
references.citation: Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16180-5
references.pmid: 12454284
references.citation: Immunol Rev. 2002 Dec;190:5-8
references.pmid: 12493002
references.citation: Nucleic Acids Res. 2003 Jan 1;31(1):311-4
references.pmid: 12520010
references.citation: J Biol Chem. 2003 Feb 14;278(7):5082-90
references.pmid: 12411439
references.citation: Eur J Immunol. 2003 Mar;33(3):639-44
references.pmid: 12616484
references.citation: J Biol Chem. 2003 Apr 18;278(16):14337-45
references.pmid: 12582157
references.citation: Placenta. 2003 Apr;24 Suppl A:S10-5
references.pmid: 12842408
references.citation: J Immunol. 2003 Aug 1;171(3):1376-84
references.pmid: 12874228
references.citation: Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):8856-61
references.pmid: 12853576
references.citation: Nat Immunol. 2003 Sep;4(9):913-9
references.pmid: 12897781
references.citation: J Exp Med. 2003 Sep 1;198(5):679-91
references.pmid: 12939341
references.citation: Tissue Antigens. 2003 Oct;62(4):273-84
references.pmid: 12974794
references.citation: Hum Immunol. 2003 Nov;64(11):999-1004
references.pmid: 14602227
references.citation: Semin Cancer Biol. 2003 Oct;13(5):317-23
references.pmid: 14708711
references.citation: Science. 1990 Apr 13;248(4952):220-3
references.pmid: 2326636
references.citation: Annu Rev Biochem. 1990;59:253-88
references.pmid: 2115762
references.citation: Mol Cell. 1998 Mar;1(4):531-41
references.pmid: 9660937
references.citation: Immunol Rev. 1998 Jun;163:129-38
references.pmid: 9700506
references.citation: Am J Reprod Immunol. 1998 Sep;40(3):136-44
references.pmid: 9764357
references.citation: Acta Crystallogr D Biol Crystallogr. 1998 Sep 1;54(Pt 5):905-21
references.pmid: 9757107
references.citation: J Immunol. 1999 Jan 1;162(1):305-13
references.pmid: 9886400
references.citation: J Exp Med. 1999 Apr 5;189(7):1093-100
references.pmid: 10190900
references.citation: Acta Crystallogr A. 1991 Mar 1;47 ( Pt 2):110-9
references.pmid: 2025413
references.citation: J Mol Biol. 1992 Apr 5;224(3):759-70
references.pmid: 1569555
references.citation: Proc Natl Acad Sci U S A. 1992 May 1;89(9):3947-51
references.pmid: 1570318
references.citation: Cell. 1993 Nov 19;75(4):693-708
references.pmid: 7694806