Review Article

Immunology and Cell Biology (2005) 83, 1–8; doi:10.1111/j.1440-1711.2005.01301.x

Structural and functional aspects of the Ly49 natural killer cell receptors

Nazzareno Dimasi1 and Roberto Biassoni1

1 Molecular Medicine Laboratory, Giannina Gaslini's Children's Institute, Genova, Italy

Correspondence: Dr Nazzareno Dimasi, Laboratorio Medicina Molecolare, Istituto Giannina Gaslini, Largo Gerolamo Gaslini 5, 16147 Genova, Italy. Email: nazzarenodimasi@ospedale-gaslini.ge.it

Received 10 June 2004; Accepted 20 September 2004.

Top

Abstract

Natural killer cells are part of the first line of innate immune defence against virus-infected cells and cancer cells in the vertebrate immune system. They are called 'natural' killers because, unlike cytotoxic T cells, they do not require a previous challenge and preactivation to become active. The Ly49 NK receptors are type II transmembrane glycoproteins, structurally characterized as disulphide-linked homodimers. They share extensive homology with C-type lectins, and they are encoded by a multigene family that in mice maps on chromosome 6. A fine balance between inhibitory and activating signals regulates the function of NK cells. Inhibitory Ly49 molecules bind primarily MHC class I ligands, whereas the ligands for activating Ly49 molecules may include MHC class I, but also interestingly MHC class I-like molecules expressed by viruses, as is the case for Ly49H, which binds the m157 gene product of murine cytomegalovirus. In this study, we review the function and X-ray crystal structure of the Ly49 NK cell receptors hitherto determined (Ly49A, Ly49C and Ly49I), and the structural features of the Ly49/MHC class I interaction as revealed by the X-ray crystal structures of Ly49A/H-2Dd and the recently determined Ly49C/H-2Kb.

Keywords:

activating receptor, crystal structure, immunoreceptor, inhibitory receptor, Ly49, Ly49/MHC complex, MHC class I, NK cell, NK cell receptor

Top

Introduction

Natural killer cells, a subset of lymphocytes, are part of the first line of defence of the innate immune system. They play a crucial role in cell-mediated immune responses in tumour cell surveillance and in host defence against pathogens. A fine balance between inhibitory and activating receptors found on the NK cell surface regulates NK cell function and cytolytic activity1, 2, 3. The predominant signal received by an NK cell through the interaction with normal levels of self MHC class I molecules expressed on the surface of target cells is inhibitory4. In contrast, when MHC class I surface expression on target cells is decreased or lacking, for example during a viral infection or as a result of tumour transformation, the inhibitory signal is attenuated and the NK cell is activated and subsequently kills the target cell.

The ability to discriminate and spare normal tissues from transformed cells was proposed some years ago by Ljunggren and Karre5, 6, 7, and is known as the 'missing self hypothesis'. This phenomenon is based on the observation that NK cells preferentially kill target cells expressing decreased levels of MHC class I molecules on their cell surface. Thus, NK-mediated surveillance for proper class I expression is determined by one or more MHC-specific inhibitory receptors that functionally dominate over the triggering signals induced by activating receptors.

Two distinct structural families of NK cell receptors are responsible for NK cell activity: the Ig-like, Ig-related receptors (KIR, LIR), and the C-type lectins (Ly49, CD94/NKG2)8, 9, 10, 11, 12. Human KIR receptors are specific for classic MHC class I molecules, while rodents and other species have evolved convergent receptors of the C-type lectin superfamily, termed Ly49, for the same function. CD94/NKG2 surface heterodimeric receptors are specific for the non-classic MHC class I molecule HLA-E. Interestingly, both types of structurally distinct NK cell surface receptor include inhibitory and activating molecules. A common feature of inhibitory receptors is the presence in their cytoplasmic region of conserved immunoreceptor tyrosine-based inhibitory motifs (ITIM). In contrast, activating NK cell receptors trigger through non-covalently linked immunoreceptor tyrosine-based activating motifs (ITAM)-bearing signal transducing polypeptides. In this review, we summarize the function and ligand specificity of both inhibitory and activating Ly49 NK receptors, with an emphasis on the structural features of these receptors as determined by X-ray crystallography.

Top

The mouse Ly49 gene family and the C-type lectin-like fold

One of the most fascinating aspects of NK function and evolution is the fact that NK cell receptors that recognize MHC class I molecules are entirely different in humans and in mice. In humans, NK cell receptors are essentially encoded by killer cell, Ig-like receptor (KIR) genes, a highly polymorphic gene family mapping on human chromosome 19, which recognizes HLA-A, HLA-B and HLA-C alleles3, 12, 13. However, mouse NK cell receptors are encoded by the C-type lectin-like Ly49 multigene family that maps on mouse distal chromosome 6, in a region termed the NK gene complex (NKC)14, 15, 16. The genes encoded within the NKC display allelic polymorphism, which in conjunction with alternative mRNA splicing results in expanding the Ly49 repertoire. It is possible that at least 23 Ly49 members exist within the NKC, Ly49A through W, for which transcripts have been determined.

Ly49 receptors are expressed at the cell surface as transmembrane disulphide-bonded homodimeric type II transmembrane proteins (Figure 1), with each chain composed of a C-type lectin-like domain (CTLD) connected to the cell membrane by an alpha-helix stalk region of approximately 70 amino acids. In the case of inhibitory Ly49 NK cell receptors, each polypeptide chain contains an ITIM tyrosine-bearing motif (Figure 1)4. After the Ly49 inhibitory receptor binds its ligand, the ITIM becomes phosphorylated in a specific tyrosine, which will recruit src homology 2 domain-containing tyrosine phosphatases (SHP)-1. This signalling cascade terminates with the inhibition of NK cytolytic activity. As shown in Figure 1, activating Ly49 NK cell receptors lack the intracellular ITIM motif; in contrast, they associate non-covalently with small disulphide-linked transmembrane homodimeric-signalling adaptor proteins termed DAP-1217. Each signalling adaptor polypeptide contains an ITAM tyrosine-based activating motif, which will recruit the Syk tyrosine kinase. This will initiate a cascade of signalling events leading to NK cell activation with subsequent killing of the target cell.

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Inhibitory and activating mouse Ly49 NK cell receptors with their intracellular signalling counterparts. Ly49 NK cell receptors are 44 kDa type II homodimeric disulphide-linked transmembrane proteins consisting of a COOH terminal extracellular C-type lectin-like domain (CTLD), connected to the cell membrane by a stalk region of approximately 70 amino acids. Upon engagement, Ly49 inhibitory receptors recruit the tyrosine phosphatase SHP-1, which in turn inhibits NK cell activation. In contrast, engagement of Ly49 activating receptors results in DAP-12 immunoreceptor tyrosine-based activating motifs (ITAM) phosphorylation, with subsequent recruitment and activation of Syk kinase. This event initiates NK cell activation.

Full figure and legend (44K)

Of the 23 existing Ly49 NK cell receptors (Table 1), 13 are inhibitory (Ly49A, B, C, E, F, G, I, J, O, Q, S, T and V), based on functional data or on the presence of the ITIM sequence in their intracytoplasmic tails. Ly49D, H, L, M, P, R, U and W are believed to be activating. The extracellular core region of inhibitory and activating Ly49 NK cell receptors is highly homologous both in amino acid sequence as well as in overall 3-D fold (Figure 2). This fold is known as the C-type lectin-like domain (CTLD), and was identified as a common feature of several different Ca2+-dependent animal lectins of which the mannose binding protein (MBP-A)18 is the prototype member. The CTLD fold consists of two alpha-helices (alpha1 and alpha2) and two antiparallel beta-sheets formed by beta-strands (beta0, beta1 and beta5; and beta2, beta2', beta3 and beta4) (Figure 2). Although the overall structural arrangement of Ly49 NK cell receptors is similar to the carbohydrate recognition domain of the animal lectin, they are not Ca2+-dependent and they do not bind carbohydrates.

Figure 2.
Figure 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Anatomy of the C-type lectin-like domains (CTLD) of Ly49 NK cell receptors. Structure of monomeric Ly49A19 (Protein Data Bank [PDB] entry code 1QO3 Chain D), monomeric Ly49C20 (PDB entry code 1P1Z Chain D) and monomeric Ly49I21 (PDB entry code 1JA3 Chain A). The secondary structural elements (alpha-helices and beta-strands), loop region, N and C termini and the disulphide bond label are shown only in Ly49A. This figure was prepared using the program Molscript34.

Full figure and legend (24K)


Top

3-D structure of monomeric Ly49A, Ly49C and Ly49I

The Ly49 NK cell receptors for which 3-D structures are presently known are Ly49A19, Ly49C20 and Ly49I21. As shown in Figure 2, the CTLD structure of these receptors is a highly conserved folding arrangement consisting of two alpha-helices (alpha1 and alpha2) and two antiparallel beta-sheets. The two beta-sheets are formed by beta-strands beta0, beta1 and beta5, and beta2, beta2', beta3 and beta4. Four intrachain disulphide bonds are conserved among the Ly49 receptors (Figure 2): Cys167–Cys253 and Cys232–Cys245 are invariant disulphides found in all C-type animal lectins9; Cys145–Cys150 is the invariant disulphide present in the long form of the C-type lectin proteins9; and Cys163–Cys251 is unique in the Ly49 proteins and links the N-terminus of strand beta5 to the helix alpha119, 20, 21. Structural differences between Ly49A, Ly49C and Ly49I are located primarily in the conformation of loop L2 and L3 (Figure 2). The most divergent loop among the Ly49 proteins is loop L3, which links beta-strand beta2' with beta-strand beta3 (residues 222–235).

Top

Structure of dimeric Ly49A, Ly49C and Ly49I: Variability in dimerization mode of the Ly49 family

The Ly49 NK cell receptors exist at the cell surface as disulphide-linked homodimers (Figure 1), stabilized by a disulphide bond between paired cysteine residues in the stalk region. The homodimeric arrangement has been shown both in solution20 and by X-ray crystallography19, 20, 21. The Ly49 homodimeric interface has a relatively high degree of shape complementarity (0.79, 0.71 and 0.72 for Ly49A, Ly49C and Ly49I, respectively), where a shape complementarity equal to 1 represents a perfect interface22. The dimer arrangement of Ly49C is similar to Ly49I, but distinct from Ly49A (Figure 3A-C).

Figure 3.
Figure 3 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Structure of the Ly49A19 (Protein Data Bank [PDB] entry code 1QO3 Chains C and D), Ly49C20 (PDB entry code 1P1Z Chain C and D) and Ly49I21 (PDB entry code 1JA3 Chain A and B) dimers. The secondary structural elements (strand beta0 and helix alpha2) involved in the dimer formation are labelled. This figure emphasizes the variability in the dimerization mode for the Ly49 NK cell receptors, where a closed dimer structural arrangement is observed for the bound Ly49A, while an open form is observed for the bound Ly49C and free Ly49I. Note the different distances between the alpha2-helices and the beta0-strands. This figure was prepared using the program Molscript34.

Full figure and legend (72K)

As shown in Figure 3, Ly49C and Ly49I subunits are linked through the first beta-strand, beta0, while the alpha-helix alpha2 is not involved in the dimer formation. Ly49C and Ly49I monomers are linked with four main chain–main chain hydrogen bonds contributed by their respective first beta-strand beta0 residues 142–14620, 21. The dimer interface includes a hydrophobic core formed by residues Trp143, Phe144 and Tyr146. In contrast to Ly49C and Ly49I, Ly49A monomers are also linked by beta-strand beta0, but the dimer interface differs in two important aspects. First, the beta0-strands in the Ly49A dimer interface are shifted by four residues compared to Ly49C and Ly49I. Second, and more importantly, the alpha2-helices are side-by-side in the Ly49A interface, closing up the Ly49A dimer (Figure 3-C). As will be discussed next, an important consequence of the variability in the Ly49 dimerization mode is to restrain the manner in which these homodimers can bind MHC class I ligands.

Top

The Ly49A/H-2Dd and Ly49C/H-2Kb complex structures and the 'cis and/or trans dilemma' interaction

The complex between Ly49A and MHC class I H-2Dd was the first structure of an NK cell receptor of the Ly49 family to be determined by X-ray crystallography19. As shown in Figure 4, Ly49A homodimers make contact with the H-2Dd ligand asymmetrically through two spatially different sites, 'site 1' and 'site 2'. The unveiling of these two distinct binding sites was unexpected, and raised several questions about which site is the functional binding site. If the chemical–physical properties of the two interfaces are analysed, site 1 (Figure 4) could fit most of the requirements to be a functional site rather than being an artefact of the protein crystallization, or an artefact induced by the truncated version of the Ly49A monomers used for crystallization19. The site 1 interface is a perfect electrostatic interface, where positive and negative charges between receptor and ligand extensively interact. In addition, site 1 is located in a region of the MHC class I H-2Dd that is highly polymorphic. In contrast, site 2 (Figure 4) resides in a cavity under the peptide-binding platform of the H-2Dd, in a region that partly overlaps the CD8 binding site23.

Figure 4.
Figure 4 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

X-ray crystal structure of Ly49A in complex with its MHC class I ligand H-2Dd (Protein Data Bank [PDB] entry code 1QO3)19 highlighting the two sites of receptor–ligand interaction. These two different binding sites were identified by X-ray crystallography19. 'Site 1' buries a total surface area of 1000 Å2 and is located at the N-terminal end of the alpha1-helix of the MHC class I molecule. This site is largely dominated by electrostatic interactions with a relatively high value for the shape correlation statistic, 0.78 (a shape complementarity value equal to 1 represents a perfect interface)22. This site was suggested to be the functional binding site, based on the high shape complementarity value and on the perfect electrostatic interactions. Subsequently, functional binding assays and site-directed mutagenesis experiments revealed that 'site 2' is the functional binding site for the Ly49A NK inhibitory receptor23, 24, 25, 26, 27. Site 2 buries a total surface area of 3300 Å2 and shows a moderately poor shape complementarity, 0.5422. This interface is primarily formed by hydrogen bond interactions. beta2m is the mouse beta2-microglobulin. This figure was prepared using the program Molscript34.

Full figure and legend (98K)

Both sites showed no direct interaction between the peptide bound to MHC class I and Ly49A homodimers (Figure 4), and this could explain the lack of peptide specificity for the Ly49A/H-2Dd interaction. In addition, the Ly49A/H-2Dd crystal structure revealed that the Ly49A binding sites do not overlap with the TCR binding area on the H-2Dd allele (reviewed in Chung et al. 24 and references therein). To answer the question of which binding site is the functional one, several research groups have examined in both functional and direct binding assays24, 25, 26, 27, 28 the Ly49A/H-2Dd interaction, using site-directed mutants of heavy chain H-2Dd, beta2-microglobulin and Ly49A. All of these experiments identified site 2 as the primary interacting surface responsible for the functional interaction between Ly49A and H-2Dd. However, the asymmetrical recognition mode of Ly49A/H-2Dd has not been determined until recently, when the crystal structure of a broadly MHC-reactive and peptide-selective Ly49C receptor bound to its ligand H-2Kb was determined by X-ray crystallography20. As shown in Figure 5, one Ly49C homodimer engages two molecules of H-2Kb in a bivalent fashion, where each Ly49C monomer makes identical interactions with MHC class I at a location that is virtually superimposable with the site 2 location in the complex Ly49A/H-2Dd (Figure 6). This clearly identifies site 2 as the functional binding site for Ly49 NK cell receptors to their MHC class I ligands. The Ly49A/H-2Dd and Ly49C/H-2Kb cocrystal structures highlighted the innate plasticity of the Ly49 homodimers to adopt a different dimerization mode in order to engage their respective ligands.

Figure 5.
Figure 5 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

X-ray crystal structure of Ly49C in complex with its MHC class I ligand H-2Kb (Protein Data Bank [PDB] entry code 1P1Z)20. This figure highlights the capacity of dimeric Ly49C to cross-link two MHC class I molecules. This type of symmetric interaction was first observed as a crystallographic interaction and subsequently has been shown to take place in solution by ultracentrifugation experiments20. The binding surface is dominated by hydrophilic and polar interaction, and buries a total solvent-accessible surface area of 2180 Å2 and shows a moderately poor shape complementarity, 0.5822. beta2m is the mouse beta2-microglobulin. This figure was prepared using the program Molscript34.

Full figure and legend (125K)

Figure 6.
Figure 6 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

MHC class I binding site for Ly49 NK cell receptors. The binding site of Ly49A/H-2Dd (dark grey), determined by X-ray crystallography and functional binding assays19, 23, 24, 25, 26, 27, was superimposed on the binding site of Ly49C/H-2Kb (light grey), as revealed by X-ray crystallography20. For clarity, only one monomer of each Ly49 molecule is shown. The superposition was obtained overlapping all alpha-carbon atoms of Ly49A monomer C and Ly49C monomer C (Protein Data Bank [PDB] entry code 1QO3 and 1P1Z, respectively). This figure highlights the fact that both Ly49 receptors 'share' a common binding site for the MHC class I ligand known as 'site 2'. This figure was prepared using the program Molscript34. For a detailed list of contact residues in Ly49A/H-2Dd and Ly49C/H-2Kb, see table 2 in Dam et al. 20

Full figure and legend (113K)

Although site 2 is accepted to be the functional binding site, there was controversy about the role of site 1 until recently when Doucey et al. 29 provided evidence that Ly49 molecules may also recognize MHC class I molecules on the NK cells themselves (a 'cis' association). This cis association could account for the site 1 interaction, while a 'trans' association could take place for site 2 interaction. Trans association takes places when the Ly49 NK cell receptor engages the MHC class I on another cell. The cis and trans models could explain the observation that the level of surface expression of Ly49 receptors is lower in mice expressing self MHC class I molecules specific for that given Ly49 receptor30.

If we assume the existence of the two conformational states for the Ly49 NK cell receptors, the question is, which one is favoured? On the surface of an NK cell, Ly49 receptors may be present both in an extended conformation that upon binding to MHC I molecules expressed on target cells inhibits NK cytolysis, and in a back-folded conformation. The latter is able to bind self alleles adjacently expressed on the surface of the same NK cells, but without generating any given inhibitory signals, indicating that the inhibitory potential of a given Ly49 receptor results from a balance between the cis and trans conformations. From a structural point of view, cis association and functional trans interaction are both mediated by site 2 Figure 4-6) and thus exclude simultaneous cis and trans interaction by a single Ly49 receptor. This cis association and trans MHC interaction may be possible only for Ly49 receptors, thanks to the length of their receptor stalk region (approximately 70 amino acids). In contrast, CD94/NKG2A has a stalk of approximately 20 residues, and KIR an even shorter stalk of only 17 amino acids. Both therefore may be structurally unable to back-fold and associate in cis like Ly49. This may explain why decreased levels of surface expression, detected by mAb staining, on NK cells expressing self-MHC alleles for that particular Ly49 receptor has never been observed for KIR or CD94/NKG2A. However, it is possible that CD94/NKG2A or KIR may associate in cis with self-ligands in a manner that is not detectable by available mAbs. It is important to stress that a requisite of the proposed model is that cis association is silent in terms of inhibitory potential, indicating that inhibition of NK cell function necessitates the simultaneous triggering of activating receptors, an event that may be possible only via the trans interaction.

Top

Conclusion

In this review we have highlighted the functional and structural aspects of the mouse Ly49 NK cell receptors. NK cells use a dual receptor system to determine whether to kill or not to kill target cells that are under stress; for example, cells transforming into tumours or infected by virus. This dual receptor system is mediated in mice in part by the Ly49 NK cell receptors; these receptors are able to deliver a positive or a negative signal. The extracellular domain of activating Ly49 receptors is very similar to those displayed by inhibitory ones, suggesting that their genes evolved by duplication and diversification events31. A marked difference in this dual receptor system resides in the transmembrane segment, where the activating receptor has a charged amino acid which permits association with ITAM-bearing signalling activating molecules. This charged amino acid is not present in the transmembrane portion of the inhibitory receptors, which are colinear with the intracellular signalling motif.

Further progress in understanding the function of NK cell receptors is in part due to X-ray crystallography. Thanks to structural work such as that reviewed here, we are able to determine precisely how an NK cell can sense its target. The structural determination of Ly49A complexed with its ligand H-2Dd is an important achievement in structural immunology, showing the presence of two distinct binding sites for Ly49A on its MHC class I H-2Dd ligand. The finding of these two binding sites was unexpected and raised several questions about which one is the primary binding site. Recently, the structure of another mouse NK cell receptor, Ly49C, complexed with one of its ligands, H-2Kb, was determined, and this finally revealed that the binding site known as site 2 is the functional binding site used by the Ly49 NK cell receptors to deliver their inhibitory or activating signals.

Another insight revealed by the Ly49 structural work is the variability in the dimerization mode within the Ly49 family. The determination of the structure of Ly49I revealed a distinct mode by which the two Ly49 monomers associate to form a stable dimer. The way in which the two monomers associate is an intrinsic ability of the Ly49 receptors, which give them the conformational plasticity needed to engage their ligands.

It will be very important in the future to determine the binding mode, through X-ray crystallography, of other Ly49 receptors to virally encoded ligands, such as the m157 gene product of mouse cytomegalovirus32, 33, which has been proven to interfere with NK cell activity through a direct binding with an activating Ly49H or an inhibitory Ly49I NK cell receptor.

Top

References

  1. Lanier LL. NK cell receptors. Annu. Rev. Immunol. 1998; 16: 359–93. | Article | PubMed | ISI | ChemPort |
  2. Yokoyama WM. Natural killer cells. In: Paul WE (ed). Fundamental Immunology. New York: Lippicot-Raven, 1999; 575–603.
  3. Biassoni R, Cantoni C, Pende D et al. Human natural killer cell receptors and coreceptors. Immunol. Rev. 2001; 181: 203–14. | Article | PubMed | ISI | ChemPort |
  4. Long EO. Regulation of immune responses through inhibitory receptors. Annu. Rev. Immunol. 1999; 17: 875–904. | Article | PubMed | ISI | ChemPort |
  5. Ljunggren HG, Karre K. Host resistance directed selectively against H-2-deficient lymphoma variants. Analysis of the mechanism. J. Exp. Med. 1985; 162: 1745–59. | Article | PubMed | ISI | ChemPort |
  6. Karre K, Ljunggren HG, Piontek G, Kiessling R. Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defense strategy. Nature 1986; 319: 675–8. | Article | PubMed | ISI | ChemPort |
  7. Ljunggren HG, Karre K. In search of the 'missing self': MHC molecules and NK cell recognition. Immunol. Today 1990; 11: 237–44. | Article | PubMed | ISI | ChemPort |
  8. Natarajan K, Dimasi N, Wang J, Mariuzza RA, Margulies DH. Structure and function of natural killer (NK) cell receptors: Multiple molecular solutions to self, non-self discrimination. Annu. Rev. Immunol. 2002; 20: 853–85. | Article | PubMed | ISI | ChemPort |
  9. Sawichi MW, Dimasi N, Natarajan K, Wang J, Margulies DH, Mariuzza RA. Structural basis of MHC class I recognition by natural killer cell receptors. Immunol. Rev. 2001; 181: 52–65. | PubMed |
  10. Biassoni R, Cantoni C, Marras D et al. Human natural killer cell receptors: insights into their molecular function and structure. J. Cell. Mol. Med. 2003; 7: 376–87. | PubMed | ISI | ChemPort |
  11. Dimasi N, Moretta L, Biassoni R. Structure of the Ly49 family of natural killer (NK) cell receptors and their interaction with MHC Class I molecules. Immunol. Res. 2004; 30: 95–104. | PubMed | ISI | ChemPort |
  12. Biassoni R, Cantoni C, Bottino C, Moretta A. Human natural killer receptors and their ligands. In: Curr. Prot. Immunol. New York: J Wiley & Sons, 2001; 1–14.10.23.
  13. Long EO, Burshtyn DN, Clark WP et al. Killer cell inhibitory receptors: Diversity, specificity and function. Immunol. Rev. 1997; 155: 135–44. | Article | PubMed | ISI | ChemPort |
  14. Takei F, Brennan J, Mager DL. The Ly49 family: genes, proteins and regulation of class I MHC. Immunol. Rev. 1997; 155: 67–77. | Article | PubMed | ISI | ChemPort |
  15. Vance RE, Tanamachi DM, Hanke T, Raulet DH. Cloning of a mouse homolog of CD94 extends the family of C-type lectins on murine natural killer cells. Eur. J. Immunol. 1997; 27: 3236–41. | PubMed | ISI | ChemPort |
  16. Yokoyama WM, Plougastel BF. Immune functions encoded by the natural killer gene complex. Nat. Rev. Immunol. 2003; 3: 304–16. | Article | PubMed | ISI | ChemPort |
  17. Smith KM, Wu J, Bakker AB, Phillips JH, Lanier LL. Ly49D and Ly49H associate with mouse DAP-12 and form activating receptors. J. Immunol. 1998; 161: 7–10. | PubMed | ISI | ChemPort |
  18. Drickamer K, Taylor ME. Biology of animal lectins. Annu. Rev. Cell. Biol. 1993; 9: 237–64. | Article | PubMed | ISI | ChemPort |
  19. Tormo J, Natarajan K, Margulies DH, Mariuzza RA. Crystal structure of a lectin-like natural killer cell receptor bound to its MHC class I ligand. Nature 1999; 402: 623–31. | Article | PubMed | ISI | ChemPort |
  20. Dam J, Guan R, Natarajan K et al. Variable MHC class I engagement by Ly49 natural killer cell receptors demonstrated by the crystal structure of Ly49C bound to H-2K(b). Nat. Immunol. 2003; 4: 1213–22. | Article | PubMed | ChemPort |
  21. Dimasi N, Sawicki MW, Reineck LA et al. Crystal structure of the Ly49I natural killer cell receptor reveals variability in dimerization mode within the Ly49 family. J. Mol. Biol. 2002; 320: 573–85. | Article | PubMed | ISI | ChemPort |
  22. Lawrence MC, Colman PM. Shape complementarity at protein/protein interfaces. J. Mol. Biol. 1993; 234: 946–50. | Article | PubMed | ISI | ChemPort |
  23. Gao GF, Tormo J, Gerth UC et al. Crystal structure of the complex between human CD8 alpha (alpha) and HLA-A2. Nature 1997; 387: 630–34. | Article | PubMed | ISI | ChemPort |
  24. Chung DH, Dorfman J, Plaksin D et al. NK and CTL recognition of a single chain H-2Dd molecule: distinct sites of H-2Dd interact with NK and TCR. J. Immunol. 1999; 163: 3699–708. | PubMed | ISI | ChemPort |
  25. Chung DH, Natarajan K, Boyd LF et al. Mapping the ligand of the NK inhibitory receptor Ly49A on living cells. J. Immunol. 2000; 165: 6922–32. | PubMed | ISI | ChemPort |
  26. Matsumoto N, Yokoyama WM, Kojima S, Yamamoto K. The NK cell MHC class I receptor Ly49A detects mutations on H-2Dd inside and outside of the peptide binding groove. J. Immunol. 2001; 166: 4422–8. | PubMed | ISI | ChemPort |
  27. Matsumoto N, Mitsuki M, Tajima K, Yokoyama WM, Yamamoto K. 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. J. Exp. Med. 2001; 193: 147–58. | Article | PubMed | ISI | ChemPort |
  28. Wang J, Whitman MC, Natarajan K, Tormo J, Mariuzza RA, Margulies DH. Binding of the natural killer cell inhibitory receptor Ly49A to its major histocompatibility complex class I ligand. Crucial contacts include both H-2Dd and beta2-microglobulin. J. Biol. Chem. 2002; 277: 1433–42. | Article | PubMed | ISI | ChemPort |
  29. Doucey M-A, Scarpellino L, Zimmer J et al. Cis association of Ly49A with MHC class I restricts natural killer cell inhibition. Nat. Immunol. 2004; 5: 328–36. | Article | PubMed | ISI | ChemPort |
  30. Zimmer J, Ioannidis V, Held W. H-2Dd ligand expression by Ly49+ natural killer (NK) cells precludes ligand uptake from environmental cells: implications for NK cell function. J. Exp. Med. 2001; 194: 1531–9. | Article | PubMed | ISI | ChemPort |
  31. Trowsdale J, Parham P. Defense strategies and immunity-related genes. Eur. J. Immunol. 2004; 34: 7–17. | Article | PubMed | ISI | ChemPort |
  32. Arase H, Mocarski ES, Campbell AE, Hill AB, Lanier LL. Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors. Science 2002; 296: 1323–6. | Article | PubMed | ISI | ChemPort |
  33. Smith HR, Heusel JW, Mehta IK et al. Recognition of a virus-encoded ligand by a natural killer cell activation receptor. Proc. Natl Acad. Sci. USA 2002; 99: 8826–31. | PubMed | ChemPort |
  34. Kraulis PJ. Molscript: a program to produce both detailed and schematic plots of protein structure. J. Appl. Crystallog. 1991; 24: 946–50. | Article | ISI |
  35. Hanke T, Takizawa H, McMahon CW et al. Direct assessment of MHC class I binding by seven Ly49 inhibitory NK cell receptors. Immunity 1999; 11: 67–77. | Article | PubMed | ISI | ChemPort |
  36. Michaelsson J, Achour A, Salcedo M et al. Visualization of inhibitory Ly49 receptor specificity with soluble major histocompatibility complex class I tetramers. Eur. J. Immunol. 2000; 30: 300–307. | Article | PubMed | ChemPort |
  37. Makrigiannis AP, Pau AT, Saleh A, Winkler-Pickett R, Ortaldo JR, Anderson SK. Class I MHC-binding characteristics of the 129/J Ly49 repertoire. J. Immunol. 2001; 166: 5034–43. | PubMed | ChemPort |
  38. Kane KP, Silver ET, Hazes B. Specificity and function of activating Ly-49 receptors. Immunol. Rev. 2001; 181: 104–14. | Article | PubMed | ISI | ChemPort |
  39. Toyama-Sorimachi N, Tsujimura Y, Maruya M et al. Ly49Q, a member of the Ly49 family that is selectively expressed on myeloid lineage cells and involved in regulation of cytoskeletal architecture. Proc. Natl Acad. Sci. USA. 2004; 101: 1016–21. | Article | PubMed | ChemPort |
Top

Acknowledgements

We are grateful to the Associazione Italiana Ricerca sul Cancro and the Consiglio Nazionale delle Ricerche for providing financial support. Nazzareno Dimasi would also like to thank the Ministero Italiano della Salute, Progetto Rientro dei Cervelli, for financial support. Nazzareno Dimasi especially wants to thank Dr Roy Mariuzza (CARB, Rockville, USA), and Dr Kannan Natarajan and Dr David Margulies (NIH, Bethesda, USA) for their scientific guidance. We would like to thank Lorenzo Moretta (Istituto Giannina Gaslini) for his scientific support.

MORE ARTICLES LIKE THIS

These links to content published by NPG are automatically generated.

NEWS AND VIEWS

Immunology Unmasking the killer's accomplice

Nature News and Views (12 Feb 1998)

Blueprints for life or death

Nature Immunology News and Views (01 May 2001)

See all 8 matches for News And Views