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首页> 外文期刊>Immunology: An Official Journal of the British Society for Immunology >Key residues at the membrane-distal surface of KACL, but not glycosylation, determine the functional interaction of the keratinocyte-specific C-type lectin-like receptor KACL with its high-affinity receptor NKp65
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Key residues at the membrane-distal surface of KACL, but not glycosylation, determine the functional interaction of the keratinocyte-specific C-type lectin-like receptor KACL with its high-affinity receptor NKp65

机译：KACL的膜远端表面上的关键残基决定了角质形成细胞特异性C型凝集素样受体KACL及其高亲和力受体NKp65的功能相互作用，而不是糖基化

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摘要

Keratinocyte-associated C-type lectin (KACL) is a peculiar C-type lectin-like receptor (CTLR) due to its selective expression by human keratinocytes and cognate interaction with the genetically coupled CTLR NKp65. KACL and NKp65 are members of the CLEC2 and NKRP1 subfamilies of natural killer gene complex (NKC)-encoded CTLR, respectively. Most NKRP1 molecules are expressed on NK cells and T cells and act as receptors of CLEC2 glycoproteins with their genes being intermingled in a certain sub-region of the mammalian NKC. The reasons for the tight genetic linkage of these dedicated receptor/ligand pairs are unknown, as is the physiological expression of NKp65. Recently, we reported that the CTLR NKp65 and KACL interact with high affinity, resulting in activation of NKp65-expressing NK-92MI cells. Here, we address the molecular basis of this high-affinity interaction by analysing KACL mutants with KACL-specific monoclonal antibodies (mAb), soluble NKp65 (sNKp65) and NK-92MI-NKp65 cells. We find that none of the three N-linked carbohydrates of KACL glycoproteins significantly contributes to KACL surface expression and NKp65 interaction. However, KACL mutants with non-conservative amino acid substitutions of arginine 158 or isoleucine 161 abrogated binding of both KACL-specific mAb OMA1 and sNKp65, well in line with the blockade of NKp65-KACL interaction by OMA1. Accordingly, functional recognition of these KACL mutants by NK-92M-NKp65 cells was completely abolished. Arginine 158 and isoleucine 161 located at the membrane-distal surface of KACL were defined as residues, decisively determining functional KACL-NKp65 interaction that is independent of KACL glycosylation.
机译：角质形成细胞相关的C型凝集素（KACL）是一种独特的C型凝集素样受体（CTLR），因为它被人角质形成细胞选择性表达并与遗传偶联的CTLR NKp65发生同源相互作用。 KACL和NKp65分别是自然杀手基因复合物（NKC）编码的CTLR的CLEC2和NKRP1子家族的成员。大部分NKRP1分子在NK细胞和T细胞上表达，并作为CLEC2糖蛋白的受体，其基因混杂在哺乳动物NKC的某个子区域中。这些专用受体/配体对紧密遗传连锁的原因尚不清楚，NKp65的生理表达也未知。最近，我们报道了CTLR NKp65和KACL具有高亲和力相互作用，导致表达NKp65的NK-92MI细胞活化。在这里，我们通过分析具有KACL特异性单克隆抗体（mAb），可溶性NKp65（sNKp65）和NK-92MI-NKp65细胞的KACL突变体，来解决这种高亲和力相互作用的分子基础。我们发现，KACL糖蛋白的三个N-连锁碳水化合物均无明显作用于KACL表面表达和NKp65相互作用。但是，具有精氨酸158或异亮氨酸161的非保守氨基酸取代的KACL突变体废除了KACL特异性mAb OMA1和sNKp65的结合，这与OMA1对NKp65-KACL相互作用的阻断非常一致。因此，完全废除了NK-92M-NKp65细胞对这些KACL突变体的功能识别。将位于KACL膜远端表面的精氨酸158和异亮氨酸161定义为残基，决定性地确定独立于KACL糖基化的功能性KACL-NKp65相互作用。

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