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Gene Review

Klra1  -  killer cell lectin-like receptor,...

Mus musculus

Synonyms: A1, CH29-493D4.3, Klra22, Ly-49, Ly-49a, ...
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Disease relevance of Klra1


High impact information on Klra1

  • One type of surface receptor such as the NKR-P1 molecule may activate NK activity whereas the other, represented by the mouse Ly-49 molecule, may engage target cell MHC molecules and inhibit cytotoxicity by transducing "negative" signals [6].
  • The Ly-49 and NKR-P1 gene families encoding lectin-like receptors on natural killer cells: the NK gene complex [6].
  • Both Ly49A binding sites on MHC-I are spatially distinct from that of the T-cell receptor [7].
  • At one interface, a single Ly49A subunit contacts one side of the MHC-I peptide-binding platform, presenting an open cavity towards the conserved glycosylation site on the H-2D(d) alpha2 domain [7].
  • We show here that the Ly49A and Ly49C NK-cell receptors are each subject to allelic exclusion [8].

Biological context of Klra1

  • Evidence for epigenetic maintenance of Ly49a monoallelic gene expression [9].
  • Screening of a 129/J cDNA library led to the discovery of 10 distinct full-length Ly49-related coding sequences (Ly49e, g, i, o, p, r, s, t, u, and v) [10].
  • Ly49 divergence should be considered when using 129-derived embryonic stem cells for the production of gene-targeted mice, especially when an immune or NK-derived phenotype is under scrutiny [10].
  • Finally, in apparent contrast to the KIR genes, we show that DNA methylation and the histone acetylation state of the Pro-2 region are strictly linked with Ly49a expression status [9].
  • NKR-P1 and Ly-49 are structurally related, and they are encoded by genetically linked loci in a chromosomal region, termed the NK gene complex (NKC), on distal mouse chromosome 6 [6].

Anatomical context of Klra1


Associations of Klra1 with chemical compounds

  • An immunoreceptor tyrosine-based inhibitory motif-containing, Ly49D-related clone was discovered that we have named Ly49O, and one immunoreceptor tyrosine-based inhibitory motif-lacking, Ly49A-related clone was discovered that we have named Ly49P [14].
  • Lymphocytes cytotoxic for HSV-infected cells lysed C57BL/6 Wt-3 cells infected with the mutant, ts A1, at 39 degrees C less efficiently than at 33 degrees C. Treatment of HSV-infected C57BL/6 Wt-3 cells with 1% 2-deoxy-D-glucose for 14 hr reduced their susceptibility to T cell-mediated lysis by 73% in the 51Cr release assay [15].
  • In examining the specificity of mouse and rat Ly49, we noticed that MHC I ligands for mouse Ly49G and W, and the rat Ly49i2, typically share the HLA-B7 supertype, defined by a B-pocket that prefers a proline at position 2 in bound peptides [16].
  • Probing with specific lectins showed that the glycoprotein contains terminal alpha-D-GalNAc, and either terminal alpha-D-NeuAc or non-terminal beta-D-(GlcNAc)2 residues, but fails to react with concanavalin A and Ulex Europeus A-1 lectins which are specific for branched alpha-D-mannose and alpha-L-fucose moieties respectively [17].
  • Mutation of tyrosine-36 to phenylalanine did not significantly affect the affinities of these proteins for the tyrosine-phosphorylated cytoplasmic tail of Ly49A [18].

Physical interactions of Klra1

  • Flow cytometric analyses of COS cells transfected with the two cDNAs showed that the 5E6 antibody binds to both Ly-49 molecules, while another anti-Ly-49C antibody, 4LO3311, binds to the newly described Ly-49C but not the previously reported Ly-49CB6 [19].
  • We have recently shown that the MHC-I ligand-binding capacity of the Ly49A NK cell receptor is controlled by the NK cells' own MHC-I [20].
  • Moreover, flow cytometry analysis of hypodiploid DNA and annexin V binding revealed that ligation of Ly49A protected cells from apoptosis induced by anti-CD3 mAbs or Ag [21].
  • We previously reported a selective deficiency of NK cells in a C57BL/6 mouse with a transgenic construct consisting of the cDNA for the Ly49A major histocompatibility complex (MHC) class 1-specific inhibitory receptor driven by the granzyme A gene [22].
  • ATF-2-binding regulatory element is responsible for the Ly49A expression in murine T lymphoid line, EL-4 [23].

Regulatory relationships of Klra1


Other interactions of Klra1

  • The Ly49I monomer adopts a fold similar to that of other C-type lectin-like NK receptors, including Ly49A, NKG2D and CD69 [28].
  • In contrast, even a higher expression of H60 molecule on the target cells failed to overcome the inhibition mediated by Ly49A/G receptors [29].
  • In addition to the previously characterized Ly49P, two new activating Ly49 proteins were discovered, Ly49R and U [10].
  • In contrast, NK cell inhibition by the MHC class I-specific receptor Ly49A was independent of Fyn, suggesting that Fyn is specifically required for NK cell activation via non-MHC receptor(s) [24].
  • Furthermore, cytotoxicity assays were performed using anti-Ly49A mAb-separated interleukin-2-activated NK cells [30].

Analytical, diagnostic and therapeutic context of Klra1

  • In contrast, ligation of the Ly49A/H chimeric receptor had no antiapoptotic effect [21].
  • Furthermore, in an experimental system based on adoptive transfer of spleen cells, receptor down-regulation of Ly49A occurred as a rapid adaptation process in mature NK cells after interaction with the H-2Dd ligand in vivo [31].
  • Polymerase chain reaction analysis revealed that although fetal NK cells are severely deficient in the expression of mRNA for Ly49A, B, C, D, G, H, and I they express high levels of Ly49E mRNA, raising the possibility that Ly49E may have an important and special function in the early development of the NK lineage [32].
  • Role of interaction between Ly49 inhibitory receptors and cognate MHC I molecules in IL2-induced development of NK cells in murine bone marrow cell cultures [33].
  • Electrophoretic mobility shift assays using oligonucleotide probes from the core Ly49i promoter and comparable regions from the Ly49a promoter demonstrated the importance of TATA-related elements in generating EL-4 and NK cell-specific DNA/protein complexes [34].


  1. Critical Residues at the Ly49 Natural Killer Receptor's Homodimer Interface Determine Functional Recognition of m157, a Mouse Cytomegalovirus MHC Class I-Like Protein. Kielczewska, A., Kim, H.S., Lanier, L.L., Dimasi, N., Vidal, S.M. J. Immunol. (2007) [Pubmed]
  2. The lymphoproliferative defect in CTLA-4-deficient mice is ameliorated by an inhibitory NK cell receptor. Chambers, C.A., Kang, J., Wu, Y., Held, W., Raulet, D.H., Allison, J.P. Blood (2002) [Pubmed]
  3. Impaired anti-viral T cell responses due to expression of the Ly49A inhibitory receptor. Zajac, A.J., Vance, R.E., Held, W., Sourdive, D.J., Altman, J.D., Raulet, D.H., Ahmed, R. J. Immunol. (1999) [Pubmed]
  4. Heterogeneous nuclear ribonucleoprotein A1 regulates RNA synthesis of a cytoplasmic virus. Shi, S.T., Huang, P., Li, H.P., Lai, M.M. EMBO J. (2000) [Pubmed]
  5. The A1 and A1B proteins of heterogeneous nuclear ribonucleoparticles modulate 5' splice site selection in vivo. Yang, X., Bani, M.R., Lu, S.J., Rowan, S., Ben-David, Y., Chabot, B. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  6. The Ly-49 and NKR-P1 gene families encoding lectin-like receptors on natural killer cells: the NK gene complex. Yokoyama, W.M., Seaman, W.E. Annu. Rev. Immunol. (1993) [Pubmed]
  7. Crystal structure of a lectin-like natural killer cell receptor bound to its MHC class I ligand. Tormo, J., Natarajan, K., Margulies, D.H., Mariuzza, R.A. Nature (1999) [Pubmed]
  8. Allelic exclusion of Ly49-family genes encoding class I MHC-specific receptors on NK cells. Held, W., Roland, J., Raulet, D.H. Nature (1995) [Pubmed]
  9. Evidence for epigenetic maintenance of Ly49a monoallelic gene expression. Rouhi, A., Gagnier, L., Takei, F., Mager, D.L. J. Immunol. (2006) [Pubmed]
  10. Class I MHC-binding characteristics of the 129/J Ly49 repertoire. Makrigiannis, A.P., Pau, A.T., Saleh, A., Winkler-Pickett, R., Ortaldo, J.R., Anderson, S.K. J. Immunol. (2001) [Pubmed]
  11. Chromosomal location of the Ly-49 (A1, YE1/48) multigene family. Genetic association with the NK 1.1 antigen. Yokoyama, W.M., Kehn, P.J., Cohen, D.I., Shevach, E.M. J. Immunol. (1990) [Pubmed]
  12. Thymus-dependent modulation of Ly49 inhibitory receptor expression on NK1.1+gamma/delta T cells. Hara, T., Nishimura, H., Hasegawa, Y., Yoshikai, Y. Immunology (2001) [Pubmed]
  13. Transgenic expression of the Ly49A natural killer cell receptor confers class I major histocompatibility complex (MHC)-specific inhibition and prevents bone marrow allograft rejection. Held, W., Cado, D., Raulet, D.H. J. Exp. Med. (1996) [Pubmed]
  14. Cloning and characterization of a novel activating Ly49 closely related to Ly49A. Makrigiannis, A.P., Gosselin, P., Mason, L.H., Taylor, L.S., McVicar, D.W., Ortaldo, J.R., Anderson, S.K. J. Immunol. (1999) [Pubmed]
  15. The involvement of herpes simplex virus type 1 glycoproteins in cell-mediated immunity. Carter, V.C., Schaffer, P.A., Tevethia, S.S. J. Immunol. (1981) [Pubmed]
  16. Cross-species dependence of ly49 recognition on the supertype defining B-pocket of a class I MHC molecule. Lavender, K.J., Kane, K.P. J. Immunol. (2006) [Pubmed]
  17. Biochemical characterization of hamster oviductin as a sulphated zona pellucida-binding glycoprotein. Malette, B., Bleau, G. Biochem. J. (1993) [Pubmed]
  18. H-2Dd engagement of Ly49A leads directly to Ly49A phosphorylation and recruitment of SHP1. Daws, M.R., Eriksson, M., Oberg, L., Ullén, A., Sentman, C.L. Immunology (1999) [Pubmed]
  19. Heterogeneity among Ly-49C natural killer (NK) cells: characterization of highly related receptors with differing functions and expression patterns. Brennan, J., Lemieux, S., Freeman, J.D., Mager, D.L., Takei, F. J. Exp. Med. (1996) [Pubmed]
  20. Interactions of Ly49 Family Receptors with MHC Class I Ligands in trans and cis. Scarpellino, L., Oeschger, F., Guillaume, P., Coudert, J.D., Lévy, F., Leclercq, G., Held, W. J. Immunol. (2007) [Pubmed]
  21. Cutting edge: Ly49A inhibits TCR/CD3-induced apoptosis and IL-2 secretion. Roger, J., Chalifour, A., Lemieux, S., Duplay, P. J. Immunol. (2001) [Pubmed]
  22. Arrested natural killer cell development associated with transgene insertion into the Atf2 locus. Kim, S., Song, Y.J., Higuchi, D.A., Kang, H.P., Pratt, J.R., Yang, L., Hong, C.M., Poursine-Laurent, J., Iizuka, K., French, A.R., Sunwoo, J.B., Ishii, S., Reimold, A.M., Yokoyama, W.M. Blood (2006) [Pubmed]
  23. ATF-2-binding regulatory element is responsible for the Ly49A expression in murine T lymphoid line, EL-4. Kubo, S., Nagasawa, R., Nishimura, H., Shigemoto, K., Maruyama, N. Biochim. Biophys. Acta (1999) [Pubmed]
  24. A role for the src family kinase Fyn in NK cell activation and the formation of the repertoire of Ly49 receptors. Lowin-Kropf, B., Kunz, B., Schneider, P., Held, W. Eur. J. Immunol. (2002) [Pubmed]
  25. Cloning and functional characteristics of murine large granular lymphocyte-1: a member of the Ly-49 gene family (Ly-49G2). Mason, L.H., Ortaldo, J.R., Young, H.A., Kumar, V., Bennett, M., Anderson, S.K. J. Exp. Med. (1995) [Pubmed]
  26. Ly-49 multigene family expressed by IL-2-activated NK cells. Smith, H.R., Karlhofer, F.M., Yokoyama, W.M. J. Immunol. (1994) [Pubmed]
  27. Receptor/ligand avidity determines the capacity of Ly49 inhibitory receptors to interfere with T-cell receptor-mediated activation. Chalifour, A., Roger, J., Lemieux, S., Duplay, P. Immunology (2003) [Pubmed]
  28. Crystal structure of the Ly49I natural killer cell receptor reveals variability in dimerization mode within the Ly49 family. Dimasi, N., Sawicki, M.W., Reineck, L.A., Li, Y., Natarajan, K., Margulies, D.H., Mariuzza, R.A. J. Mol. Biol. (2002) [Pubmed]
  29. NKG2D receptor-mediated NK cell function is regulated by inhibitory Ly49 receptors. Regunathan, J., Chen, Y., Wang, D., Malarkannan, S. Blood (2005) [Pubmed]
  30. Ly49A allelic variation and MHC class I specificity. Mehta, I.K., Wang, J., Roland, J., Margulies, D.H., Yokoyama, W.M. Immunogenetics (2001) [Pubmed]
  31. External and internal calibration of the MHC class I-specific receptor Ly49A on murine natural killer cells. Kåse, A., Johansson, M.H., Olsson-Alheim, M.Y., Kärre, K., Höglund, P. J. Immunol. (1998) [Pubmed]
  32. MHC class I expression protects target cells from lysis by Ly49-deficient fetal NK cells. Toomey, J.A., Shrestha, S., de la Rue, S.A., Gays, F., Robinson, J.H., Chrzanowska-Lightowlers, Z.M., Brooks, C.G. Eur. J. Immunol. (1998) [Pubmed]
  33. Role of interaction between Ly49 inhibitory receptors and cognate MHC I molecules in IL2-induced development of NK cells in murine bone marrow cell cultures. Das, A., Saxena, R.K. Immunol. Lett. (2004) [Pubmed]
  34. Characterization of the Ly49I promoter. Gosselin, P., Makrigiannis, A.P., Nalewaik, R., Anderson, S.K. Immunogenetics (2000) [Pubmed]
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