Charaterization of the Expression and Ligands of KIR3DS1

KIR3DS1 表达和配体的表征

• 批准号: 7592901
• 负责人: Daniel W. McVicar
• 金额: $ 23.55万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7592901
• 关键词: Acquired Immunodeficiency Syndrome; Activated Natural Killer Cell; Alleles; Antibodies; Antiviral Response; Binding; Biochemical; Cells; Characteristics; Cytoplasmic Tail; Development; Disease; Dissection; Epitopes; Extracellular Domain; Frequencies; Genes; Goals; HIV; HIV therapy; HIV-1; HLA-Bw4; Immune response; Immune system; Individual; Infection; KIR3DS1; Lead; Ligand Binding; Ligands; Mutate; NK Cell Activation; NK cell receptor NKB1; Natural Killer Cells; Numbers; Peptides; Play; Proteins; Regulation; Role; Screening procedure; Site; Specificity; Structure; Therapeutic; Viremia; Work; killer immunoglobulin-like receptor; novel strategies; receptor; three dimensional structure

KIR3DS1 is presumed to be an NK cell activation receptor. The gene has many (>40) inhibitory alleles, known as KIR3DL1. Various KIR3DL1 subtypes have been shown to interact directly with HLA-I proteins with the Bw4 public epitope. Regardless of its similarity to KIR3DL1, and its established role in HIV disease, KIR3DS1 has only recently been shown to be expressed on NK cells and no ligand has been described. Toward an understanding of KIR3DS1 ligand binding we have been conducting studies using Bw4 HLA-I tetramers folded with various peptides. These studies have, thus far, demonstrated no binding to KIR3DS1. Therefore, we have used several new alleles of KIR3DL1 as a guide for a mutagenic study of KIR3DS1. In this work specific residues of KIR3DS1 are mutated to match various residues of KIR3DL1. We evaluate the ability of KIR3D specific antibodies and HLA tetramers to recognize these new KIR3DL1 species and superimpose these findings on the presumed three dimensional structure of KIR3DL1. Through this analysis we can define specific sites on KIR3DS1 that control the ligand binding specificity and draw conclusions regarding its ligand. The high frequency of KIR3DS1 we have previously described, together with this receptors ability to activate NK cells and be maintained during HIV viremia, suggest that our dissection of its binding characteristics will lead to exciting new approaches to HIV therapy.

KIR3DS1 被认为是 NK 细胞激活受体。该基因有许多（>40）抑制性等位基因，称为 KIR3DL1。各种 KIR3DL1 亚型已被证明可直接与具有 Bw4 公共表位的 HLA-I 蛋白相互作用。不管它与 KIR3DL1 的相似性及其在 HIV 疾病中的作用如何，KIR3DS1 最近才被证明在 NK 细胞上表达，并且没有描述配体。为了了解 KIR3DS1 配体结合，我们一直在使用与各种肽折叠的 Bw4 HLA-I 四聚体进行研究。迄今为止，这些研究已证明与 KIR3DS1 没有结合。因此，我们使用 KIR3DL1 的几个新等位基因作为 KIR3DS1 诱变研究的指导。在这项工作中，KIR3DS1 的特定残基被突变以匹配 KIR3DL1 的各种残基。我们评估了 KIR3D 特异性抗体和 HLA 四聚体识别这些新 KIR3DL1 物种的能力，并将这些发现叠加在 KIR3DL1 的假定三维结构上。通过此分析，我们可以定义 KIR3DS1 上控制配体结合特异性的特定位点，并得出有关其配体的结论。我们之前描述的 KIR3DS1 的高频率，以及这种受体激活 NK 细胞并在 HIV 病毒血症期间维持的能力，表明我们对其结合特征的剖析将带来令人兴奋的 HIV 治疗新方法。