Reciprocal Transfer of Class I MHC Allele Specificity between Activating Ly-49P and Ly-49W Receptors by Exchange of β4–β5 Loop Residues

Brian, Johnny E.; Silver, Elizabeth T.; Hazes, Bart; Kane, Kevin P.

doi:10.4049/jimmunol.171.10.5337

Cited by 7 publications

(9 citation statements)

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“…2 and 7), provide support for subsite C contributing to allele specificity of Ly49 interaction. Furthermore, our previous findings showed that substituting a sequence within the ␤4-␤5 loop of Ly49W for that of another Ly49 receptor, Ly49P, allows the mutant Ly49P to recognize a new MHC I allele product (43,52). Because the ␤4-␤5 loop of Ly49P and W, similar to Ly49A (Fig.…”

Section: Discussionmentioning

confidence: 99%

Distinctive Interactions at Multiple Site 2 Subsites by Allele-Specific Rat and Mouse Ly49 Determine Functional Binding and Class I MHC Specificity

Lavender

Chau

Kane

2007

The Journal of Immunology

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Rodent Ly49 exhibit allele-specific MHC I recognition, yet the interaction site, site 2, encompassing the area below the MHC peptide-binding groove, the α3 domain, and associated β2 microglobulin, is highly conserved among rat and mouse MHC I alleles. We previously demonstrated that allele-specific Ly49 recognition can be affected by polymorphisms specifically in the peptide anchor-binding and supertype-defining B pocket of MHC I, possibly through differential conformations assumed by solvent-exposed interaction residues when articulating with this pocket. Through mutagenesis of RT1-A1c and H-2Dd, we map for the first time the interaction site(s) on rat MHC I mediating rat Ly49i2 recognition and the previously unexamined Ly49GBALB/c interaction with H-2Dd. We demonstrate that rat Ly49i2 and mouse Ly49G use both unique and common interactions at three MHC I H chain subsites to mediate functional binding and allele-specific recognition. We find that the F subsite, formed by solvent-exposed residues below the more conserved C-terminal anchor residue-binding F pocket, acts as an anchoring location for both Ly49i2 and Ly49G, whereas these receptors exhibit distinctive reliance on solvent-exposed residues articulating with the polymorphic anchor-binding and supertype-defining pocket(s) at subsite B, as well as on interaction residues at subsite C in the MHC I α3 domain. Our findings, combined with previous Ly49A/H-2Dd and Ly49C/H-2Kb cocrystal data, suggest how allele-specific MHC I conformations and Ly49 polymorphisms may affect Ly49 placement on MHC I ligands and residue usage at site 2, thereby mediating allele-specific recognition at the highly conserved MHC I interface.

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Section: Discussionmentioning

confidence: 99%

Distinctive Interactions at Multiple Site 2 Subsites by Allele-Specific Rat and Mouse Ly49 Determine Functional Binding and Class I MHC Specificity

Lavender

Chau

Kane

2007

The Journal of Immunology

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“…Overlaid onto these primary interactions are secondary ones involving L6, which displays considerable sequence variability within each group. As demonstrated by mutational analysis (30), L6 regulates the specificity of Ly49s for particular H-2D or H-2K alleles, most likely by modifying the affinity derived from conserved interactions. However, it is not apparent which allele-specific features of MHC-I are detected by L6.…”

Section: Structure Of the Ly49c-h-2k Bmentioning

confidence: 99%

“…However, it is not apparent which allele-specific features of MHC-I are detected by L6. In the Ly49A-H-2D d structure, all MHC-I residues within 10 Å of L6 are identical between H-2D d and H-2D k , yet amino acid changes in L6 alone suffice to alter the specificity of Ly49s for these alleles (29,30). Because H-2D…”

Section: Structure Of the Ly49c-h-2k Bmentioning

confidence: 99%

Molecular Architecture of the Major Histocompatibility Complex Class I-binding Site of Ly49 Natural Killer Cell Receptors

Deng

Cho

Malchiodi

et al. 2008

Journal of Biological Chemistry

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The cytolytic activity of NK cells is regulated by a delicate balance of activating and inhibitory signals mediated through distinct classes of receptors found on their surface. The dominant signal received by an NK cell through its interaction with normal levels of major histocompatibility complex class I (MHC-I) molecules on target cells is inhibitory. If the level of MHC-I is reduced through tumorigenic or infectious processes, this inhibitory signal is attenuated, and the NK cell is activated (1-3). In this way, cells with abnormal MHC-I expression become targets of NK lytic activity.Several receptor families have been identified on primate and rodent NK cells that monitor MHC-I expression on surrounding cells (3-5). These include the killer immunoglobulin-like receptors, members of the Ly49 family (Ly49s), and the CD94-NKG2 family of receptors. Additionally, the activating receptor NKG2D recognizes MHC-like molecules, such as MICA, that are up-regulated in stressed tissues (6). The mouse Ly49 family includes at least 23 expressed or potential members (Ly49A-W), along with about 15 allelic variants (2, 7). These highly polymorphic receptors constitute the main MHC-monitoring molecules on rodent NK cells. Although most Ly49s inhibit NK cell-mediated cytolysis after binding to MHC-I ligands, some are activating. Ly49s recognize one or more H-2D or H-2K alleles, independently of the MHC-bound peptide (2, 3). Their binding properties range from the broad recognition of MHC-I molecules by Ly49C to the allelic specificity of Ly49A. Recently, crucial roles for Ly49 receptors in antiviral immunity have been discovered. In one case, the m157 gene product of mouse cytomegalovirus (MCMV) was shown to interact directly with an inhibitory Ly49 (Ly49I) in a susceptible mouse strain and with an activating Ly49 (Ly49H) in a resistant one (8, 9). In another case, the activating receptor Ly49P was found to confer resistance to MCMV by interacting with H-2D molecules on MCMV-infected cells (10).Ly49 receptors belong to the C-type lectin-like family of proteins, which also includes CD94-NKG2 and NKG2D (4, 5). Ly49s are homodimeric type II glycoproteins, with each chain composed of a C-type lectin-like domain, termed the natural killer receptor domain (NKD), connected by a stalk of ϳ70 residues to the transmembrane and cytoplasmic domains. Crystal structures have been reported for Ly49A bound to H-2D d (11) and for Ly49C bound to H-2K b (12). These structures showed that both Ly49s engage MHC-I at a broad cavity beneath the * This work was supported, in whole or in part, by National Institutes of Health Grant AI047990. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. The atomic coordinates and structure factors (codes 3C8J, 3CAD, and 3C8K)

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“…The identity of the insert was verified by DNA sequencing. RNK-16 cells were stably transfected with the construct as previously described (21). Positive expression of Ly49Wi2 was verified by surface staining with STOK2 (anti-Ly49i2) Ab by flow cytometry.…”

Section: Generation Of Rnk-16 Effector Cells Expressing Chimeric Ly49mentioning

confidence: 99%

Recognition of Class I MHC by a Rat Ly49 NK Cell Receptor Is Dependent on the Identity of the P2 Anchor Amino Acid of Bound Peptide

Brian

Kane

2011

The Journal of Immunology

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Members of the rodent Ly49 receptor family control NK cell responsiveness and demonstrate allele specificity for MHC class I (MHC-I) ligands. For example, the rat Ly49i2 inhibitory NK cell receptor binds RT1-A1c but not other rat MHC class Ia or Ib molecules. RT1-A1c preferentially binds peptides with proline at the second, or P2, position, which defines it as an HLA-B7 supertype MHC-I molecule. Previously, our laboratory showed that mutations within the MHC-I supertype-defining B-pocket of RT1-A1c could lead to alterations in P2 anchor residues of the peptide repertoire bound by RT1-A1c and loss of recognition by Ly49i2. Although suggestive of peptide involvement, it was unclear whether the peptide P2 anchor residue or alteration of the RT1-A1c primary sequence influenced Ly49i2 recognition. Therefore, we directly investigated the role of the P2 anchor residue of RT1-A1c–bound peptides in Ly49i2 recognition. First, fluorescent multimers generated by refolding soluble recombinant RT1-A1c with individual synthetic peptides differing only at the P2 anchor residue were examined for binding to Ly49i2 NK cell transfectants. Second, cytotoxicity by Ly49i2-expressing NK cells toward RMA-S target cells expressing RT1-A1c bound with peptides that only differ at the P2 anchor residue was evaluated. Our results demonstrate that Ly49i2 recognizes RT1-A1c bound with peptides that have Pro or Val at P2, whereas little or no recognition is observed when RT1-A1c is complexed with peptide bearing Gln at P2. Thus, the identity of the P2 peptide anchor residue is an integral component of MHC-I recognition by Ly49i2.

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Reciprocal Transfer of Class I MHC Allele Specificity between Activating Ly-49P and Ly-49W Receptors by Exchange of β4–β5 Loop Residues

Cited by 7 publications

References 50 publications

Distinctive Interactions at Multiple Site 2 Subsites by Allele-Specific Rat and Mouse Ly49 Determine Functional Binding and Class I MHC Specificity

Distinctive Interactions at Multiple Site 2 Subsites by Allele-Specific Rat and Mouse Ly49 Determine Functional Binding and Class I MHC Specificity

Molecular Architecture of the Major Histocompatibility Complex Class I-binding Site of Ly49 Natural Killer Cell Receptors

Recognition of Class I MHC by a Rat Ly49 NK Cell Receptor Is Dependent on the Identity of the P2 Anchor Amino Acid of Bound Peptide

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