Crystal structure of a complete ternary complex of T-cell receptor, peptide-MHC, and CD4
Crystal structure of a complete ternary complex of T-cell receptor, peptide-MHC, and CD4
复制标题
DOI：
10.1073/pnas.1118801109
复制
发表时间：
2012-04-03
影响因子：
11.1
通讯作者：
Mariuzza, Roy A.
中科院分区：
文献类型：
--
作者：
Yin, Yiyuan;Wang, Xin Xiang;Mariuzza, Roy A.
获得性免疫依赖于T细胞受体(TCR)对与抗原提呈细胞(APC)上的主要组织相容性复合体(PMHC)分子结合的抗原肽的特异性识别。此外，T细胞的激活通常需要将相同的pMHC与CD4或CD8共受体结合。在这里，我们报告了一个完整的TCR-pMHC-CD4三元复合体的结构，它包括一个人自身免疫性TCR，一种结合到HLA-DR4上的髓鞘来源的自体多肽，以及CD4。该复合体类似于一个尖形拱门，其中TCR和CD4各自相对于T细胞膜倾斜65度。通过排除TCR和CD4之间的直接接触，该结构解释了T细胞上的TCR和CD4如何同时又独立地与APC上的相同pMHC结合。该结构与之前的突变数据相结合，将TCR相关的CD3 epsilon Gamma和CD3 epsilon Delta亚基放置在TCR-pMHC-CD4拱门内，面向CD4，向T细胞传递激活信号。通过在T细胞膜上建立TCR和CD4的锚点，该复合体为了解在胸腺T细胞选择过程中CD4辅助受体如何将TCR聚集在MHC上以指导TCR对接在pMHC上提供了基础。
Adaptive immunity depends on specific recognition by a T-cell receptor (TCR) of an antigenic peptide bound to a major histocompatibility complex (pMHC) molecule on an antigen-presenting cell (APC). In addition, T-cell activation generally requires binding of this same pMHC to a CD4 or CD8 coreceptor. Here, we report the structure of a complete TCR-pMHC-CD4 ternary complex involving a human autoimmune TCR, a myelin-derived self-peptide bound to HLA-DR4, and CD4. The complex resembles a pointed arch in which TCR and CD4 are each tilted similar to 65 degrees relative to the T-cell membrane. By precluding direct contacts between TCR and CD4, the structure explains how TCR and CD4 on the T cell can simultaneously, yet independently, engage the same pMHC on the APC. The structure, in conjunction with previous mutagenesis data, places TCR-associated CD3 epsilon gamma and CD3 epsilon delta subunits, which transmit activation signals to the T cell, inside the TCR-pMHC-CD4 arch, facing CD4. By establishing anchor points for TCR and CD4 on the T-cell membrane, the complex provides a basis for understanding how the CD4 coreceptor focuses TCR on MHC to guide TCR docking on pMHC during thymic T-cell selection.