Characterization of the Expression and Ligands of KIR3DS1

KIR3DS1被认为是一种NK细胞活化受体。该基因有许多抑制性等位基因，称为KIR3DL1。各种KIR3DL1亚型已被证明与具有Bw4公共表位的hla - 1蛋白直接相互作用。尽管其与KIR3DS1的相似性及其在HIV疾病中的既定作用，但KIR3DS1尚未确定该受体的直接配体。我们继续剖析明显缺乏KIR3DS1与HLA-Bw4结合的生化基础。KIR3DL1与HLA-Bw4结合，而高度相关的KIR3DS1则不结合。因此，我们与一个团队合作，解决了KIR3DL1的晶体结构，进行了靶向诱变，确定了控制KIR3DL1/HLA-Bw4结合的残基。利用从这些研究中获得的信息，我们预测了可能促进KIR3DS1与Bw5结合的肽。我们测试了多种多肽，并确定了其中3种有效。这些肽首次证明了Bw4和KIR3DS1之间的直接相互作用。除了我们对KIR3DL1/S1的研究外，我们开始将这一分析扩展到KIR3DL2，这是一种与强直性脊柱炎和皮肤淋巴瘤相关的受体。我们已经描述了一些KIR3DL2等位基因的差异表达，并正在与合作者合作将这些等位基因与疾病联系起来。此外，我们正在开始对KIR3DL2信号传导及其功能的生物化学研究。

KIR3DS1 is presumed to be an NK cell activation receptor. The gene has many 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 no direct ligand of this receptor has been identified. We continue to dissect the biochemical basis of the apparent lack of KIR3DS1 binding to HLA-Bw4. KIR3DL1 binds to HLA-Bw4 but the highly related KIR3DS1 does not. Therefore, we have carried out targeted mutagenesis that defines the residues controlling KIR3DL1/HLA-Bw4 binding by collaborating with a group that solved the crystal structure of KIR3DL1. Using the information gained from these studies we predicted peptides that might facilitate binding of KIR3DS1 by Bw5. We tested multiple peptides and identified 3 that work. These peptides represent the first demonstration of direct interaction between Bw4 and KIR3DS1. In addition to our work on KIR3DL1/S1 we begun to extend this analysis to KIR3DL2, a related receptor implicated in ankylosing spondylitis and cutaneous lymphoma. We have described differential expression of some KIR3DL2 alleles and are working with collaborators in connecting these alleles to disease. In addition, we are beginning study of the biochemistry of KIR3DL2 signaling and function.