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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Structural elucidation of the m157 mouse cytomegalovirus ligand for Ly49 natural killer cell receptors
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Structural elucidation of the m157 mouse cytomegalovirus ligand for Ly49 natural killer cell receptors

机译：Ly157自然杀伤细胞受体的m157小鼠巨细胞病毒配体的结构解析

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摘要

Natural killer (NK) cells express activating and inhibitory receptors that, in concert, survey cells for proper expression of cell surface major histocompatibility complex (MHC) class I molecules. The mouse cytomegalovirus encodes an MHC-like protein, m157, which is the only known viral antigen to date capable of engaging both activating (Ly49H) and inhibitory (Ly49I) NK cell receptors. We have determined the 3D structure of m157 and studied its biochemical and cellular interactions with the Ly49H and Ly49I receptors. m157 has a characteristic MHC-fold, yet possesses several unique structural features not found in other MHC class I-like molecules. m157 does not bind peptides or other small ligands, nor does it associate with β_2-microglobulin. Instead, m157 engages in extensive intra-and intermolecular interactions within and between its domains to generate a compact minimal MHC-like molecule. m157's binding affinity for Ly49I (K_d ≈ 0.2 μM) is significantly higher than that of classical inhibitory Ly49-MHC interactions. Analysis of viral escape mutations on m157 that render it resistant to NK killing reveals that it is likely to be recognized by Ly49H in a binding mode that differs from Ly49/MHC-I. In addition, Ly49H+ NK cells can efficiently lyse RMA cells expressing m157, despite the presence of native MHC class I. Collectively, our results show that m157 represents a structurally divergent form of MHC class I-like proteins that directly engage Ly49 receptors with appreciable affinity in a noncanonical fashion.
机译：自然杀伤（NK）细胞表达激活受体和抑制受体，一致地，它们会调查细胞中细胞表面主要组织相容性复合体（MHC）I类分子的正确表达。小鼠巨细胞病毒编码一种MHC样蛋白m157，这是迄今为止已知的唯一能够与激活（Ly49H）和抑制（Ly49I）NK细胞受体结合的病毒抗原。我们已经确定了m157的3D结构，并研究了其与Ly49H和Ly49I受体的生化和细胞相互作用。 m157具有特征性的MHC折叠，但具有其他MHC I类分子中未发现的几个独特的结构特征。 m157不结合肽或其他小的配体，也不与β_2-微球蛋白缔合。相反，m157在其结构域内和结构域之间参与广泛的分子内和分子间相互作用，以生成紧凑的最小MHC样分子。 m157对Ly49I的结合亲和力（K_d≈0.2μM）显着高于经典抑制性Ly49-MHC相互作用。对m157上使它对NK杀伤具有抗性的病毒逃逸突变的分析表明，它可能以不同于Ly49 / MHC-1的结合方式被Ly49H识别。此外，尽管存在天然的I类MHC，Ly49H + NK细胞也可以有效地裂解表达m157的RMA细胞。总的来说，我们的结果表明，m157代表结构多样的MHC类I类蛋白，其以明显的亲和力直接与Ly49受体结合。以非规范的方式。

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