A Mechanical Switch Couples T Cell Receptor Triggering to the Cytoplasmic Juxtamembrane Regions of CD3ζζ.
A Mechanical Switch Couples T Cell Receptor Triggering to the Cytoplasmic Juxtamembrane Regions of CD3ζζ.
复制标题
DOI：
10.1016/j.immuni.2015.06.018
复制
发表时间：
2015-08-18
期刊：
影响因子：
32.4
通讯作者：
Kuhns MS
中科院分区：
文献类型：
--
作者：
Lee MS;Glassman CR;Deshpande NR;Badgandi HB;Parrish HL;Uttamapinant C;Stawski PS;Ting AY;Kuhns MS
八亚单位T细胞受体(TCR)-CD3复合体是决定T细胞命运的主要决定因素。然而，它如何通过细胞膜传递配体特有的信息以转换为化学信号仍未解决。我们假设TCR的参与触发了相关CD3亚单位之间的空间关系的改变，这些亚单位在连接处从膜进入细胞质。利用基于ID-Prime、FRET和EpoR活性的三种原位邻近分析方法，我们确定了CD3TCRCD3亚基的胞质膜旁区域在组装成ζζ-CD3复合体时是分散的。然后，TCR参与触发了他们的并列。这种机械开关位于启动化学信号的CD3ζζ胞内基序的上游，以及调节信号增强的多元延伸。这些发现提供了一个框架，可以用来检查激活免疫受体和其他复杂分子机器的触发事件。
The eight-subunit T cell receptor (TCR)-CD3 complex is the primary determinant for T cell fate decisions. Yet how it relays ligand-specific information across the cell membrane for conversion to chemical signals remains unresolved. We hypothesized that TCR engagement triggers a change in the spatial relationship between the associated CD3ζζ subunits at the junction where they emerge from the membrane into the cytoplasm. Using three in situ proximity assays based on ID-PRIME, FRET, and EPOR activity we determined that the cytosolic juxtamembrane regions of the CD3ζζ subunits are spread apart upon assembly into the TCR-CD3 complex. TCR engagement then triggered their apposition. This mechanical switch resides upstream of the CD3ζζ intracellular motifs that initiate chemical signaling as well as the polybasic stretches that regulate signal potentiation. These findings provide a framework from which to examine triggering events for activating immune receptors and other complex molecular machines.