Structural basis of assembly of the human T cell receptor-CD3 complex
Structural basis of assembly of the human T cell receptor-CD3 complex
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人T细胞受体-CD3复合物组装的结构基础
DOI：
10.1038/s41586-019-1537-0
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发表时间：
2019-09-26
期刊：
影响因子：
64.8
通讯作者：
Huang, Zhiwei
中科院分区：
文献类型：
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作者：
Dong, De;Zheng, Lvqin;Huang, Zhiwei
α β T细胞受体（TCR）与CD 3 γ ε-CD 3 δ ε-CD 3 ζ ζ信号传导六聚体相关，是T细胞发育和活化以及对外来抗原的免疫应答的主要决定因素。TCR-CD 3复合物的组装机制仍然未知。在这里，我们报告了一个冷冻电子显微镜结构的人TCR α β在复杂的CD 3六聚体在3.7埃的分辨率。该结构包含完整的细胞外结构域和TCR-CD 3的所有跨膜螺旋。八聚体TCR-CD 3复合物以1：1：1：1化学计量的TCR α β：CD 3 γ β：CD 3 ζ：CD 3 ζ组装。TCR-CD 3的胞外结构域的组装由TCR α β的恒定结构域和连接肽介导，所述TCR α β的连接肽与CD 3 γ ε-CD 3 δ β包装，形成靠近质膜的三聚体样结构。CD 3复合物的跨膜段采用由CD 3 zeta zeta的两个跨膜螺旋与CD 3 gamma β和CD 3 delta β的跨膜螺旋相互作用形成的桶状结构。TCR α β的跨膜螺旋通过疏水和离子相互作用插入桶样结构中导致TCR-⑶ 3复合物的跨膜组装。总之，我们的数据揭示了TCR-CD 3复合物组装的结构基础，为TCR触发提供了线索，并为靶向该复合物的免疫疗法的合理设计奠定了基础。
The alpha beta T cell receptor (TCR), in association with the CD3 gamma epsilon-CD3 delta epsilon-CD3 zeta zeta signalling hexamer, is the primary determinant of T cell development and activation, and of immune responses to foreign antigens. The mechanism of assembly of the TCR-CD3 complex remains unknown. Here we report a cryo-electron microscopy structure of human TCR alpha beta in complex with the CD3 hexamer at 3.7 angstrom resolution. The structure contains the complete extracellular domains and all the transmembrane helices of TCR-CD3. The octameric TCR-CD3 complex is assembled with 1:1:1:1 stoichiometry of TCR alpha beta:CD3 gamma epsilon:CD3 zeta zeta:CD3 zeta zeta. Assembly of the extracellular domains of TCR-CD3 is mediated by the constant domains and connecting peptides of TCR alpha beta that pack against CD3 gamma epsilon-CD3 delta epsilon, forming a trimer-like structure proximal to the plasma membrane. The transmembrane segment of the CD3 complex adopts a barrel-like structure formed by interaction of the two transmembrane helices of CD3 zeta zeta with those of CD3 gamma epsilon and CD3 delta epsilon. Insertion of the transmembrane helices of TCR alpha beta into the barrel-like structure via both hydrophobic and ionic interactions results in transmembrane assembly of the TCR-CD3 complex. Together, our data reveal the structural basis for TCR-CD3 complex assembly, providing clues to TCR triggering and a foundation for rational design of immunotherapies that target the complex.