KIR3DS1-specific D0 domain polymorphisms disrupt KIR3DL1 surface expression and HLA binding Journal Article
| Authors: | Mulrooney, T. J.; Zhang, A. C.; Goldgur, Y.; Boudreau, J. E.; Hsu, K. C. |
| Article Title: | KIR3DS1-specific D0 domain polymorphisms disrupt KIR3DL1 surface expression and HLA binding |
| Abstract: | KIR3DL1 is a polymorphic inhibitory receptor that modulates NK cell activity through interacting with HLA-A and HLA-B alleles that carry the Bw4 epitope. Amino acid polymorphisms throughout KIR3DL1 impact receptor surface expression and affinity for HLA. KIR3DL1/S1 encodes inhibitory and activating alleles, but despite high homology with KIR3DL1, the activating receptor KIR3DS1 does not bind the same ligand. Allele KIR3DL1∗009 resulted from a gene recombination event between the inhibitory receptor allele KIR3DL1∗001 and the activating receptor allele KIR3DS1∗013. This study analyzed the functional impact of KIR3DS1-specific polymorphisms on KIR3DL1∗009 surface expression, binding to HLA, and functional capacity. Flowcytometric analysis of primary human NK cells as well as transfected HEK293T cells shows that KIR3DL1∗009 is expressed at a significantly lower surface density compared with KIR3DL1∗001. Using recombinant proteins of KIR3DL1∗001, KIR3DL1∗009, and KIR3DS1∗013 to analyze binding to HLA, we found that although KIR3DL1∗009 displayed some evidence of binding to HLA compared with KIR3DS1∗013, the binding was minimal compared with KIR3DL1∗001 and KIR3DL1∗005. Mutagenesis of polymorphic sites revealed that the surface phenotype and reduced binding of KIR3DL1∗009 are caused by the combined amino acid polymorphisms at positions 58 and 92 within the D0 extracellular domain. Resulting from these effects, KIR3DL1∗009+ NK cells exhibited significantly less inhibition by HLA-Bw4+ target cells compared with KIR3DL1∗001+ NK cells. The data from this study contribute novel insight into how KIR3DS1-specific polymorphisms in the extracellular region impact KIR3DL1 surface expression, ligand binding, and inhibitory function. Copyright © 2015 by The American Association of Immunologists, Inc. |
| Keywords: | controlled study; protein expression; human cell; flow cytometry; protein conformation; protein domain; embryo; molecular dynamics; protein binding; natural killer cell; amino acid; ligand binding; mutagenesis; hla antigen; hla system; protein polymorphism; surface property; killer cell immunoglobulin like receptor 3ds1; killer cell immunoglobulin like receptor 3dl1; human; priority journal; article |
| Journal Title: | Journal of Immunology |
| Volume: | 195 |
| Issue: | 3 |
| ISSN: | 0022-1767 |
| Publisher: | The American Association of Immunologists, Inc |
| Date Published: | 2015-08-01 |
| Start Page: | 1242 |
| End Page: | 1250 |
| Language: | English |
| DOI: | 10.4049/jimmunol.1500243 |
| PROVIDER: | scopus |
| PMCID: | PMC4506867 |
| PUBMED: | 26109640 |
| DOI/URL: | |
| Notes: | Export Date: 2 September 2015 -- Source: Scopus |
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