MHC class I recognition by NK receptors in the Ly49 family is strongly influenced by the beta 2-microglobulin subunit.
NK cell recognition of targets is strongly affected by MHC class I specific receptors. The recently published structure of the inhibitory receptor Ly49A in complex with H-2Dd revealed two distinct sites of interaction in the crystal. One of these involves the alpha1, alpha2, alpha3, and beta2-microglobulin (beta2m) domains of the MHC class I complex. The data from the structure, together with discrepancies in earlier studies using MHC class I tetramers, prompted us to study the role of the beta2m subunit in MHC class I-Ly49 interactions. Here we provide, to our knowledge, the first direct evidence that residues in the beta2m subunit affect binding of MHC class I molecules to Ly49 receptors. A change from murine beta2m to human beta2m in three different MHC class I molecules, H-2Db, H-2Kb, and H-2Dd, resulted in a loss of binding to the receptors Ly49A and Ly49C. Analysis of the amino acids involved in the binding of Ly49A to H-2Dd in the published crystal structure, and differing between the mouse and the human beta2m, suggests the cluster formed by residues Lys3, Thr4, Thr28, and Gln29, as a potentially important domain for the Ly49A-H-2Dd interaction. Another possibility is that the change of beta2m indirectly affects the conformation of distal parts of the MHC class I molecule, including the alpha1 and alpha2 domains of the heavy chain.
Michaëlsson
J
J
Microbiology and Tumor Biology Center, Karolinska Institutet, Stockholm, Sweden. jakob.michaelsson@mtc.ki.se
Achour
A
A
Rölle
A
A
Kärre
K
K
D000595:Amino Acid Sequence; D000818:Animals; D000950:Antigens, Ly; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002461:Cell Line, Transformed; D006183:H-2 Antigens / Q000378:metabolism; D064532:Histocompatibility Antigen H-2D; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D006825:Hybridomas; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D055650:NK Cell Lectin-Like Receptor Subfamily A; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D017510:Protein Folding; D051381:Rats; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D055630:Receptors, NK Cell Lectin-Like; D014162:Transfection; D014407:Tumor Cells, Cultured; D001613:beta 2-Microglobulin / Q000235:genetics / Q000502:physiology*
D000950:Antigens, Ly; D002352:Carrier Proteins; D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; D015395:Histocompatibility Antigens Class I; C527088:Klra1 protein, mouse; C527091:Klra3 protein, mouse; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D055650:NK Cell Lectin-Like Receptor Subfamily A; D011971:Receptors, Immunologic; D055630:Receptors, NK Cell Lectin-Like; D001613:beta 2-Microglobulin