title: CD94-NKG2A recognition of human leukocyte antigen (HLA)-E bound to an HLA class I leader sequence.
abstract: The recognition of human leukocyte antigen (HLA)-E by the heterodimeric CD94-NKG2 natural killer (NK) receptor family is a central innate mechanism by which NK cells monitor the expression of other HLA molecules, yet the structural basis of this highly specific interaction is unclear. Here, we describe the crystal structure of CD94-NKG2A in complex with HLA-E bound to a peptide derived from the leader sequence of HLA-G. The CD94 subunit dominated the interaction with HLA-E, whereas the NKG2A subunit was more peripheral to the interface. Moreover, the invariant CD94 subunit dominated the peptide-mediated contacts, albeit with poor surface and chemical complementarity. This unusual binding mode was consistent with mutagenesis data at the CD94-NKG2A-HLA-E interface. There were few conformational changes in either CD94-NKG2A or HLA-E upon ligation, and such a "lock and key" interaction is typical of innate receptor-ligand interactions. Nevertheless, the structure also provided insight into how this interaction can be modulated by subtle changes in the peptide ligand or by the pairing of CD94 with other members of the NKG2 family. Differences in the docking strategies used by the NKG2D and CD94-NKG2A receptors provided a basis for understanding the promiscuous nature of ligand recognition by NKG2D compared with the fidelity of the CD94-NKG2 receptors.
authors.affiliation: The Protein Crystallography Unit, ARC Centre of Excellence in Structural and Functional Microbial Genomics, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Petrie
authors.forename: Craig S
authors.initials: CS
authors.lastname: Clements
authors.forename: Jie
authors.initials: J
authors.lastname: Lin
authors.forename: Lucy C
authors.initials: LC
authors.lastname: Sullivan
authors.forename: Darryl
authors.initials: D
authors.lastname: Johnson
authors.forename: Trevor
authors.initials: T
authors.lastname: Huyton
authors.forename: Annie
authors.initials: A
authors.lastname: Heroux
authors.forename: Hilary L
authors.initials: HL
authors.lastname: Hoare
authors.forename: Travis
authors.initials: T
authors.lastname: Beddoe
authors.forename: Hugh H
authors.initials: HH
authors.lastname: Reid
authors.forename: Matthew C J
authors.initials: MC
authors.lastname: Wilce
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Brooks
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006680:HLA Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D046912:Multiprotein Complexes; D055654:NK Cell Lectin-Like Receptor Subfamily C; D051920:NK Cell Lectin-Like Receptor Subfamily D / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011485:Protein Binding; D021382:Protein Sorting Signals / Q000235:genetics; D021122:Protein Subunits; D011971:Receptors, Immunologic / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D055607:Receptors, Natural Killer Cell; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D055672:Static Electricity; D000097625:HLA-E Antigens
chemical_list: D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; D046912:Multiprotein Complexes; D055654:NK Cell Lectin-Like Receptor Subfamily C; D051920:NK Cell Lectin-Like Receptor Subfamily D; D055655:NK Cell Lectin-Like Receptor Subfamily K; D021382:Protein Sorting Signals; D021122:Protein Subunits; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D011994:Recombinant Proteins; D000097625:HLA-E Antigens; C527054:KLRC1 protein, human; C497869:KLRD1 protein, human; C527085:KLRK1 protein, human