Identification of a crucial energetic footprint on the al helix of human histocompatibility leukocyte antigen (HLA)-A2 that provides functional interactions for recognition by tax peptide/HLA-A2-specifrc T cell receptors
Identification of a crucial energetic footprint on the al helix of human histocompatibility leukocyte antigen (HLA)-A2 that provides functional interactions for recognition by tax peptide/HLA-A2-specifrc T cell receptors
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DOI：
10.1084/jem.193.5.551
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发表时间：
2001-03-05
影响因子：
15.3
通讯作者：
Biddison, WE
中科院分区：
文献类型：
--
作者：
Baker, BM;Turner, RV;Biddison, WE
结构研究表明，I类主要组织相容性复合体（MHC）限制性肽特异性T细胞受体（TCR）-α/β与MHC的α 1和α 2螺旋进行多次接触，但尚不清楚这些相互作用中的哪些或多少有助于功能结合。我们已经通过对人类组织相容性白细胞抗原（HLA）-A2分子上的15个TCR接触位点进行单氨基酸诱变来解决这个问题，所述人类组织相容性白细胞抗原（HLA）-A2分子被对HLA-A2呈递的Tax肽具有特异性的A6 TCR识别。结果表明，只有三个氨基酸（R65，K66和A69），聚集在α 1螺旋的诱变影响T细胞的税收/HLA-A2复合物的识别。这三种突变体中至少有一种影响了Tax/HLA-A2特异性T细胞系的每个成员对T细胞的识别。Biacore测量显示，这三种HLA-A2突变也改变了A6 TCR结合动力学，降低了结合亲和力。这些结果表明，对于Tax/HLA-A2特异性TCR，在α 1螺旋的中心部分存在一个位置，该位置提供了对它们与MHC分子的功能至关重要的相互作用。
Structural studies have shown that class I major histocompatibility complex (MHC)-restricted peptide-specific T cell receptor (TCR)-alpha/betas make multiple contacts with the alpha1 and alpha2 helices of the MHC, but it is unclear which or how many of these interactions contribute to functional binding. We have addressed this question by performing single amino acid mutagenesis of the 15 TCR contact sites on the human histocompatibility leukocyte antigen (HLA)-A2 molecule recognized by the A6 TCR specific for the Tax peptide presented by HLA-A2. The results demonstrate that mutagenesis of only three amino acids (R65, K66, and A69) that are clustered on the alpha1 helix affected T cell recognition of the Tax/HLA-A2 complex. At least one of these three mutants affected T cell recognition by every member of a large panel of Tax/HLA-A2-specific T cell lines. Biacore measurements showed that these three HLA-A2 mutations also altered A6 TCR binding kinetics, reducing binding affinity. These results show that for Tax/HLA-A2-specific TCRs, there is a location on the central portion of the alpha1 helix that provides interactions crucial to their function with the MHC molecule.