Dimorphic Motifs in D0 and D1+D2 Domains of Killer Cell Ig-Like Receptor 3DL1 Combine to Form Receptors with High, Moderate, and No Avidity for the Complex of a Peptide Derived from HIV and HLA-A*2402

Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
The Journal of Immunology (Impact Factor: 4.92). 10/2009; 183(7):4569-82. DOI: 10.4049/jimmunol.0901734
Source: PubMed


Comparison of mutant killer cell Ig-like receptor (KIR) 3DL1*015 substituted at natural positions of variation showed that tryptophan/leucine dimorphism at position 283 uniquely changes receptor conformation and can strongly influence binding of the A24nef tetramer. Dimorphic motifs at positions 2, 47, and 54 in D0 and 182 and 283 in D1+D2 distinguish the two 3DL1 lineages, typified by 3DL1*005 and 3DL1*015. The interlineage recombinant, KIR3DL1*001, combines D0 of 3DL1*005 with D1+D2 of 3DL1*015 and binds A24nef more strongly than either parent. In contrast, the reciprocal recombinant with D0 from 3DL1*015 and D1+D2 from 3DL1*005 cannot bind A24nef. Thus, D0 polymorphism directly affects the avidity of the KIR3DL1 ligand binding site. From these observations, multiple sequence alignment, and homology modeling, we constructed structural models for KIR3DL1 and its complex with A24nef. In these models, D0, D1, and D2 come together to form a binding surface for A24nef, which is contacted by all three Ig-like domains. A central pocket binds arginine 83, the only Bw4 motif residue essential for KIR3DL1 interaction, similar to the binding of lysine 80 in HLA-C by KIR2DL1. Central to this interaction is a salt bridge between arginine 83 of Bw4 and glutamate 282 of 3DL1, which juxtaposes the functionally influential dimorphism at position 283. Further 3DL1 mutants were tested and shown to have A24nef-binding properties consistent with the models. A24nef was not bound by KIR3DS1, the activating counterpart of KIR3DL1. Moreover, introducing any one of three residues specific to KIR3DS1, serine 163, arginine 166, or leucine 199, into 3DL1*015, abrogated A24nef binding.

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Available from: Paul J Norman, Oct 13, 2015
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    • "In hematopoietic stem cell transplantation, specific KIR loci have been shown to have an impact on outcome, and adoptive therapy based on KIR/ligand reactivity has been used for the treatment of malignant relapse [27], [28], [29]. Given that KIR allelic products have been shown to differ in their specificity for and affinity of ligand binding [30], [31], these allelic differences may translate into differences in disease progression [26], [32], [33]. "
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    ABSTRACT: The immune responses of natural killer cells are regulated, in part, by killer cell immunoglobulin-like receptors (KIR). The 16 closely-related genes in the KIR gene system have been diversified by gene duplication and unequal crossing over, thereby generating haplotypes with variation in gene copy number. Allelic variation also contributes to diversity within the complex. In this study, we estimated allele-level haplotype frequencies and pairwise linkage disequilibrium statistics for 14 KIR loci. The typing utilized multiple methodologies by four laboratories to provide at least 2x coverage for each allele. The computational methods generated maximum-likelihood estimates of allele-level haplotypes. Our results indicate the most extensive allele diversity was observed for the KIR framework genes and for the genes localized to the telomeric region of the KIR A haplotype. Particular alleles of the stimulatory loci appear to be nearly fixed on specific, common haplotypes while many of the less frequent alleles of the inhibitory loci appeared on multiple haplotypes, some with common haplotype structures. Haplotype structures cA01 and/or tA01 predominate in this cohort, as has been observed in most populations worldwide. Linkage disequilibrium is high within the centromeric and telomeric haplotype regions but not between them and is particularly strong between centromeric gene pairs KIR2DL5∼KIR2DS3S5 and KIR2DS3S5∼KIR2DL1, and telomeric KIR3DL1∼KIR2DS4. Although 93% of the individuals have unique pairs of full-length allelic haplotypes, large genomic blocks sharing specific sets of alleles are seen in the most frequent haplotypes. These high-resolution, high-quality haplotypes extend our basic knowledge of the KIR gene system and may be used to support clinical studies beyond single gene analysis.
    PLoS ONE 11/2012; 7(11):e47491. DOI:10.1371/journal.pone.0047491 · 3.23 Impact Factor
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    • "Despite the high level of homology to KIR3DL1, KIR3DS1 differs in at least six amino acid positions throughout the extracellular domains, including positions 163, 166 (D1 domain), and 199 (D2 domain; Gardiner et al., 2001). Introduction of any of these KIR3DS1-specific amino acid residues into a KIR3DL1*001 molecule as performed by Sharma et al. (2009) led to complete abrogation of binding to HLA-A*2402, a confirmed ligand for KIR3DL1. In this context, Thomas et al. (2008) identified a natural KIR3DL1 allotype (KIR3DL1*054) that shares the same amino acid residues at position 138, 163, and 166 of the D1 domain with KIR3DS1*013. "
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    ABSTRACT: The function of natural killer (NK) cells is controlled by several activating and inhibitory receptors, including the family of killer-immunoglobulin-like receptors (KIRs). One distinctive feature of KIRs is the extensive number of various haplotypes generated by the gene content within the KIR gene locus as well as by highly polymorphic members of the KIR gene family, namely KIR3DL1/S1. Within the KIR3DL1/S1 gene locus, KIR3DS1 represents a conserved allelic variant and displays other unique features in comparison to the highly polymorphic KIR3DL1 allele. KIR3DS1 is present in all human populations and belongs to the KIR haplotype group B. KIR3DS1 encodes for an activating receptor featuring the characteristic short cytoplasmic tail and a positively charged residue within the transmembrane domain, which allows recruitment of the ITAM-bearing adaptor molecule DAP12. Although HLA class I molecules are thought to represent natural KIR ligands, and HLA-Bw4 molecules serve as ligands for KIR3DL1, the ligand for KIR3DS1 still needs to be identified. Despite the lack of formal evidence for an interaction of KIR3DS1 with HLA-Bw4-I80 or any other HLA class I subtype to date, a growing number of associations between the presence of KIR3DS1 and the outcome of viral infections have been described. Especially, the potential protective role of KIR3DS1 in combination with HLA-Bw4-I80 in the context of HIV-1 infection has been studied intensively. In addition, a number of recent studies have associated the presence or absence of KIR3DS1 with the occurrence and outcome of some malignancies, autoimmune diseases, and graft-versus-host disease (GVHD). In this review, we summarize the present knowledge regarding the characteristics of KIRD3S1 and discuss its role in various human diseases.
    Frontiers in Immunology 11/2012; 3:326. DOI:10.3389/fimmu.2012.00326
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    • "These sequences are of interest because they share this motif with a sequence previously found only in cynomolgus macaques (Macaca fascicularis) (EU419113). The unique residues for these sequences (186-193) correspond to predicted MHC class I binding sites [41]. These sequences may represent an additional macaque KIR gene, or a lineage within KIR3DS03. "
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    ABSTRACT: Human killer immunoglobulin-like receptors (KIRs) play a critical role in governing the immune response to neoplastic and infectious disease. Rhesus macaques serve as important animal models for many human diseases in which KIRs are implicated; however, the study of KIR activity in this model is hindered by incomplete characterization of KIR genetics. Here we present a characterization of KIR genetics in rhesus macaques (Macaca mulatta). We conducted a survey of KIRs in this species, identifying 47 novel full-length KIR sequences. Using this expanded sequence library to build upon previous work, we present evidence supporting the existence of 22 Mamu-KIR genes, providing a framework within which to describe macaque KIRs. We also developed a novel pyrosequencing-based technique for KIR genotyping. This method provides both comprehensive KIR genotype and frequency estimates of transcript level, with implications for the study of KIRs in all species. The results of this study significantly improve our understanding of macaque KIR genetic organization and diversity, with implications for the study of many human diseases that use macaques as a model. The ability to obtain comprehensive KIR genotypes is of basic importance for the study of KIRs, and can easily be adapted to other species. Together these findings both advance the field of macaque KIRs and facilitate future research into the role of KIRs in human disease.
    BMC Genomics 06/2011; 12(1):295. DOI:10.1186/1471-2164-12-295 · 3.99 Impact Factor
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