The functional binding site for the C-type lectin-like natural killer cell receptor Ly49A spans three domains of its major histocompatibility complex class I ligand.
Natural killer (NK) cells express receptors that recognize major histocompatibility complex (MHC) class I molecules and regulate cytotoxicity of target cells. In this study, we demonstrate that Ly49A, a prototypical C-type lectin-like receptor expressed on mouse NK cells, requires species-specific determinants on beta2-microglobulin (beta2m) to recognize its mouse MHC class I ligand, H-2D(d). The involvement of beta2m in the interaction between Ly49A and H-2D(d) is also demonstrated by the functional effects of a beta2m-specific antibody. We also define three residues in alpha1/alpha2 and alpha3 domains of H-2D(d) that are critical for the recognition of H-2D(d) on target cells by Ly49A. In the crystal structure of the Ly49A/H-2D(d) complex, these residues are involved in hydrogen bonding to Ly49A in one of the two potential Ly49A binding sites on H-2D(d). These data unambiguously indicate that the functional effect of Ly49A as an MHC class I-specific NK cell receptor is mediated by binding to a concave region formed by three structural domains of H-2D(d), which partially overlaps the CD8 binding site.
Matsumoto
N
N
Laboratory of Molecular Medicine, Department of Integrated Biosciences, The University of Tokyo Graduate School of Frontier Sciences, Tokyo 113-0033, Japan. nmatsu@k.u-tokyo.ac.jp
Mitsuki
M
M
Tajima
K
K
Yokoyama
W M
WM
Yamamoto
K
K
D000818:Animals; D000950:Antigens, Ly; D001483:Base Sequence; D001665:Binding Sites; D016827:CD8 Antigens / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D006183:H-2 Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D064532:Histocompatibility Antigen H-2D; D006801:Humans; D066298:In Vitro Techniques; D007694:Killer Cells, Natural / Q000276:immunology*; D037102:Lectins / Q000378:metabolism*; D037181:Lectins, C-Type; D008024:Ligands; D046911:Macromolecular Substances; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D055650:NK Cell Lectin-Like Receptor Subfamily A; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011971:Receptors, Immunologic / Q000737:chemistry / Q000378:metabolism*; D055630:Receptors, NK Cell Lectin-Like; D014162:Transfection; D001613:beta 2-Microglobulin / Q000276:immunology
D000950:Antigens, Ly; D016827:CD8 Antigens; D002352:Carrier Proteins; D017931:DNA Primers; D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; C527088:Klra1 protein, mouse; D037102:Lectins; D037181:Lectins, C-Type; D008024:Ligands; D046911:Macromolecular Substances; D008565:Membrane Proteins; D055650:NK Cell Lectin-Like Receptor Subfamily A; D011971:Receptors, Immunologic; D055630:Receptors, NK Cell Lectin-Like; D001613:beta 2-Microglobulin