title: Binding of the natural killer cell inhibitory receptor Ly49A to its major histocompatibility complex class I ligand. Crucial contacts include both H-2Dd AND beta 2-microglobulin.
abstract: Ly49A, an inhibitory C-type lectin-like mouse natural killer cell receptor, functions through interaction with the major histocompatibility complex class I molecule, H-2D(d). The x-ray crystal structure of the Ly49A.H-2D(d) complex revealed that homodimeric Ly49A interacts at two distinct sites of H-2D(d): Site 1, spanning one side of the alpha1 and alpha2 helices, and Site 2, involving the alpha1, alpha2, alpha3, and beta(2)m domains. Mutants of Ly49A, H-2D(d), and beta(2)-microglobulin at intermolecular contacts and the Ly49A dimer interface were examined for binding affinity and kinetics. Although mutations at Site 1 had little affect, several at Site 2 and at the dimer interface hampered the Ly49A.H-2D(d) interaction, with no effect on gross structure or T cell receptor interaction. The region surrounding the most critical residues (in H-2D(d), Asp(122); in Ly49A, Asp(229), Ser(236), Thr(238), Arg(239), and Asp(241); and in beta(2)-microglobulin, Gln(29) and Lys(58)) of the Ly49A.H-2D(d) interface at Site 2 includes a network of water molecules, suggesting a molecular basis for allelic specificity in natural killer cell recognition.
authors.affiliation: Molecular Biology Section, Laboratory of Immunology, NIAID, National Institutes of Health, Bethesda, Maryland 20892-1892, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Mary C
authors.initials: MC
authors.lastname: Whitman
authors.forename: Kannan
authors.initials: K
authors.lastname: Natarajan
authors.forename: Jose
authors.initials: J
authors.lastname: Tormo
authors.forename: Roy A
authors.initials: RA
authors.lastname: Mariuzza
authors.forename: David H
authors.initials: DH
authors.lastname: Margulies
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D000950:Antigens, Ly; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D006183:H-2 Antigens / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D064532:Histocompatibility Antigen H-2D; D007694:Killer Cells, Natural / Q000502:physiology; D037181:Lectins, C-Type; D008024:Ligands; D008285:Major Histocompatibility Complex / Q000502:physiology; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D055650:NK Cell Lectin-Like Receptor Subfamily A; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D055630:Receptors, NK Cell Lectin-Like; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020349:Surface Plasmon Resonance; D001613:beta 2-Microglobulin / Q000235:genetics / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D000950:Antigens, Ly; D000954:Antigens, Surface; D002352:Carrier Proteins; D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; C527088:Klra1 protein, mouse; D037181:Lectins, C-Type; D008024:Ligands; D008565:Membrane Proteins; D055650:NK Cell Lectin-Like Receptor Subfamily A; D011971:Receptors, Immunologic; D055630:Receptors, NK Cell Lectin-Like; D011994:Recombinant Proteins; D001613:beta 2-Microglobulin