Natural variation at position 45 in the D1 domain of lineage III killer cell immunoglobulin-like receptors (KIR) has major effects on the avidity and specificity for MHC class I
Natural variation at position 45 in the D1 domain of lineage III killer cell immunoglobulin-like receptors (KIR) has major effects on the avidity and specificity for MHC class I
复制标题
DOI：
10.1007/s00251-011-0527-7
复制
发表时间：
2011-08-01
期刊：
影响因子：
3.2
通讯作者：
Parham, Peter
中科院分区：
文献类型：
--
作者：
Aguilar, Anastazia M. Older;Guethlein, Lisbeth A.;Parham, Peter
D1结构域中44位的替代赖氨酸和甲硫氨酸残基决定了人类谱系III杀伤细胞免疫球蛋白样受体（KIR）对HLA-C的C1和C2表位的特异性。具有谷氨酸44的KIR也存在于猩猩（Popy 2DLB）和黑猩猩（Pt-2DL 9）中，但明显不存在于人类中。Popy 2DLB对C1和C2表位都表现出广泛的特异性，而Pt-2DL 9对C2具有狭窄的特异性。Popy 2DLB中的苯丙氨酸45突变为Pt-2DL 9中存在的半胱氨酸残基足以将Popy 2DLB特异性缩小至与Pt-2DL 9相似。相比之下，用苯丙氨酸替换Pt-2DL 9中的半胱氨酸45对其C2特异性没有影响，但降低了亲合力。以类似的方式，在具有赖氨酸44并识别C1的Popy 2DLA中用半胱氨酸替换苯丙氨酸45，保持了这种特异性，同时降低了亲合力。位置45是异常可变的，展示了区分不同谱系和物种的KIR的12个残基。我们的研究表明，在位置45的变化，以调节KIR亲合力和HLA-C的特异性的潜力。位置45突变的各种效应与其中具有谷氨酸44和对C1和C2的广泛特异性的Popy 2DLB样受体促进C2表位从C1表位和C2特异性KIR从C1特异性KIR的进化的模型一致。随着C2和C2特异性受体的获得，针对这种广泛特异性受体的选择导致其从人类系中丢失，并缩小其在黑猩猩系中的特异性。
Alternative lysine and methionine residues at position 44 in the D1 domain determine the specificities of human lineage III killer cell immunoglobulin-like receptors (KIR) for the C1 and C2 epitopes of HLA-C. KIR having glutamate 44 are also present in orangutans (Popy2DLB) and chimpanzees (Pt-2DL9) but notably absent from humans. Popy2DLB exhibits broad specificity for both the C1 and C2 epitopes, whereas Pt-2DL9 has narrow specificity for C2. Mutation of phenylalanine 45 in Popy2DLB to the cysteine residue present in Pt-2DL9 was sufficient to narrow the Popy2DLB specificity to be like that of Pt-2DL9. In contrast, replacement of cysteine 45 in Pt-2DL9 by phenylalanine had no effect on its C2 specificity, but reduced the avidity. In a similar manner, replacement of phenylalanine 45 with cysteine in Popy2DLA, which has lysine 44 and recognizes C1, maintained this specificity while reducing avidity. Position 45 is exceptionally variable, exhibiting twelve residues that distinguish KIR of different lineages and species. Our study demonstrates the potential for variation at position 45 to modulate KIR avidity and specificity for HLA-C. The various effects of position 45 mutation are consistent with a model in which a Popy2DLB-like receptor, having glutamate 44 and broad specificity for C1 and C2, facilitated the evolution of the C2 epitope from the C1 epitope and C2-specific KIR from C1-specific KIR. With the acquisition of C2 and C2-specific receptors, the selection against this broadly specific receptor led to its loss from the human line and narrowing of its specificity on the chimpanzee line.