A Cholesterol-Based Allostery Model of T Cell Receptor Phosphorylation
A Cholesterol-Based Allostery Model of T Cell Receptor Phosphorylation
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DOI：
10.1016/j.immuni.2016.04.011
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发表时间：
2016-05-17
期刊：
影响因子：
32.4
通讯作者：
Schamel, Wolfgang W. A.
中科院分区：
文献类型：
--
作者：
Swamy, Mahima;Beck-Garcia, Katharina;Schamel, Wolfgang W. A.
通过T细胞受体（TCR）的信号传导控制适应性免疫应答。抗原与TCR α β的结合通过质膜传递信号，以通过不完全理解的机制诱导CD 3胞质尾的磷酸化。在这里，我们表明，胆固醇结合到TCR β跨膜区保持TCR在一个休息，非活性构象，不能被磷酸化的活性激酶。只有自发脱离胆固醇的TCR可以转换为活性构象（称为引发的TCR），然后被磷酸化。事实上，通过基因或酶促调节胆固醇结合，我们可以在静息状态和启动状态之间切换TCR。活性构象通过与肽-MHC结合而稳定，从而控制TCR信号传导。这些数据解释了一个模型的相互变构调节TCR磷酸化胆固醇和配体结合。我们的研究结果提供了一个分子机制和一个概念框架，脂质受体相互作用如何调节信号转导。
Signaling through the T cell receptor (TCR) controls adaptive immune responses. Antigen binding to TCR alpha beta transmits signals through the plasma membrane to induce phosphorylation of the CD3 cytoplasmic tails by incompletely understood mechanisms. Here we show that cholesterol bound to the TCR beta transmembrane region keeps the TCR in a resting, inactive conformation that cannot be phosphorylated by active kinases. Only TCRs that spontaneously detached from cholesterol could switch to the active conformation (termed primed TCRs) and then be phosphorylated. Indeed, by modulating cholesterol binding genetically or enzymatically, we could switch the TCR between the resting and primed states. The active conformation was stabilized by binding to peptide-MHC, which thus controlled TCR signaling. These data are explained by a model of reciprocal allosteric regulation of TCR phosphorylation by cholesterol and ligand binding. Our results provide both a molecular mechanism and a conceptual framework for how lipid-receptor interactions regulate signal transduction.