Structural basis for NKG2A/CD94 recognition of HLA-E
Structural basis for NKG2A/CD94 recognition of HLA-E
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DOI：
10.1073/pnas.0802736105
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发表时间：
2008-05-06
影响因子：
11.1
通讯作者：
Strong, Roland K.
中科院分区：
文献类型：
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作者：
Kaiser, Brett K.;Pizarro, Juan Carlos;Strong, Roland K.
NKG 2x/CD 94（x = A、C、E）天然巨噬细胞受体通过与HILA-E复合物结合在免疫监视中发挥重要作用，HILA-E复合物专门呈递来自MIHC I类前导序列的肽，从而监测MHC I类表达。我们以4.4埃的分辨率确定了NKG 2A/CD 94/HLA-E复合物的晶体结构，揭示了这种相互作用的两个关键方面。首先，肽的C-末端区域，其显示出最大的可变性。在I类前导序列中，完全与这些受体的不变组分CD 94相互作用。其次，NKG 2A/C的残基167-170导致抑制性NKG 2A/CD 94受体的亲和力比其活化性NKG 2C/CD 94对应物高约6倍。这些残基不直接接触HLA-E或肽，而是形成与CD 94的异二聚体界面的一部分。灵长类动物的进化分析表明，CD 94是在纯化选择下进化的，而NKG 2A和NKG 2C都是在正选择下进化的。具体而言，在CD 94接口的残基已经进化下积极的选择，这表明这些基因的进化是由病原体衍生的配体的相互作用。与这种可能性一致，我们表明NKG 2C/CD 94，而不是NKG 2A/CD 94，与CMV MHC同源物UL 18弱但特异性结合。因此，NKG 2x/CD 94受体家族的进化可能是由结合不变HLA-E配体的需要和避免病原体源性诱饵破坏的需要形成的。
The NKG2x/CD94 (x = A, C, E) natural killer-cell receptors perform an important role in immunosurveillance by binding to HILA-E complexes that exclusively present peptides derived from MIHC class I leader sequences, thereby monitoring MHC class I expression. We have determined the crystal structure of the NKG2A/CD94/HLA-E complex at 4.4-angstrom resolution, revealing two critical aspects of this interaction. First, the C-terminal region of the peptide, which displays the most variability. among class I leader sequences, interacts entirely with CD94, the invariant component of these receptors. Second, residues 167-170 of NKG2A/C account for the approximate to 6-fold-higher affinity of the inhibitory NKG2A/CD94 receptor compared to its activating NKG2C/CD94 counterpart. These residues do not contact HLA-E or peptide directly but instead form part of the heterodimer interface with CD94. An evolutionary analysis across primates reveals that whereas CD94 is evolving under purifying selection, both NKG2A and NKG2C are evolving under positive selection. Specifically, residues at the CD94 interface have evolved under positive selection, suggesting that the evolution of these genes is driven by an interaction with pathogen-derived ligands. Consistent with this possibility, we show that NKG2C/CD94, but not NKG2A/CD94, weakly but specifically binds to the CMV MHC-homologue UL18. Thus, the evolution of the NKG2x/CD94 family of receptors has likely been shaped both by the need to bind the invariant HLA-E ligand and the need to avoid subversion by pathogen-derived decoys.