Guo Xingdong, Yan Chengsong, Li Hua, Huang Wenmao, Shi Xiaoshan, Huang Min, Wang Yingfang, Pan Weiling, Cai Mingjun, Li Lunyi, Wu Wei, Bai Yibing, Zhang Chi, Liu Zhijun, Wang Xinyan, Zhang Xiaohui F, Tang Chun, Wang Hongda, Liu Wanli, Ouyang Bo, Wong Catherine C, Cao Yi, Xu Chenqi
State Key Laboratory of Molecular Biology, Shanghai Science Research Center, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
Collaborative Innovation Center of Advanced Microstructures, National Laboratory of Solid State Microstructure and Department of Physics, Nanjing University, Nanjing, Jiangsu 210093, China.
Cell Res. 2017 Apr;27(4):505-525. doi: 10.1038/cr.2017.42. Epub 2017 Mar 24.
T-cell receptor-CD3 complex (TCR) is a versatile signaling machine that can initiate antigen-specific immune responses based on various biochemical changes of CD3 cytoplasmic domains, but the underlying structural basis remains elusive. Here we developed biophysical approaches to study the conformational dynamics of CD3ε cytoplasmic domain (CD3ε). At the single-molecule level, we found that CD3ε could have multiple conformational states with different openness of three functional motifs, i.e., ITAM, BRS and PRS. These conformations were generated because different regions of CD3ε had heterogeneous lipid-binding properties and therefore had heterogeneous dynamics. Live-cell imaging experiments demonstrated that different antigen stimulations could stabilize CD3ε at different conformations. Lipid-dependent conformational dynamics thus provide structural basis for the versatile signaling property of TCR.
T细胞受体-CD3复合物（TCR）是一种多功能信号传导机器，它可以基于CD3胞质结构域的各种生化变化引发抗原特异性免疫反应，但其潜在的结构基础仍然难以捉摸。在这里，我们开发了生物物理方法来研究CD3ε胞质结构域（CD3ε）的构象动力学。在单分子水平上，我们发现CD3ε可以具有多种构象状态，其三个功能基序（即免疫受体酪氨酸活化基序（ITAM）、碱性残基富集序列（BRS）和脯氨酸残基富集序列（PRS））具有不同的开放程度。这些构象的产生是因为CD3ε的不同区域具有异质的脂质结合特性，因此具有异质的动力学。活细胞成像实验表明，不同的抗原刺激可以使CD3ε稳定在不同的构象。因此，脂质依赖性构象动力学为TCR的多功能信号特性提供了结构基础。
