W.M. Keck Laboratory for Structural Biology, University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, MD 20850, USA; Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA.
W.M. Keck Laboratory for Structural Biology, University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, MD 20850, USA; Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA.
J Mol Biol. 2020 Dec 4;432(24):166697. doi: 10.1016/j.jmb.2020.10.031. Epub 2020 Nov 4.
T cells are vital for adaptive immune responses that protect against pathogens and cancers. The T cell receptor (TCR)-CD3 complex comprises a diverse αβ TCR heterodimer in noncovalent association with three invariant CD3 dimers. The TCR is responsible for recognizing antigenic peptides bound to MHC molecules (pMHC), while the CD3 dimers relay activation signals to the T cell. However, the mechanisms by which TCR engagement by pMHC is transmitted to CD3 remain mysterious, although there is growing evidence that mechanosensing and allostery both play a role. Here, we carried out NMR analysis of a human autoimmune TCR (MS2-3C8) that recognizes a self-peptide from myelin basic protein presented by the MHC class II molecule HLA-DR4. We observed pMHC-induced NMR signal perturbations in MS2-3C8 that indicate long-range effects on TCR β chain conformation and dynamics. Our results demonstrate that, in addition to expected changes in the NMR resonances of pMHC-contacting residues, perturbations extend to the Vβ/Vα, Vβ/Cβ, and Cβ/Cα interfacial regions. Moreover, the pattern of long-range perturbations is similar to that detected previously in the β chains of two MHC class I-restricted TCRs, thereby revealing a common allosteric pathway among three unrelated TCRs. Molecular dynamics (MD) simulations predict similar pMHC-induced effects. Taken together, our results demonstrate that pMHC binding induces long-range allosteric changes in the TCR β chain at conserved sites in both representative MHC class I- and class II-restricted TCRs, and that these sites may play a role in the transmission of signaling information.
T 细胞对于适应性免疫反应至关重要，这种反应可以保护机体免受病原体和癌症的侵害。T 细胞受体（TCR）-CD3 复合物由非共价结合的多样化的 αβ TCR 异二聚体与三个不变的 CD3 二聚体组成。TCR 负责识别与 MHC 分子结合的抗原肽（pMHC），而 CD3 二聚体将激活信号转导至 T 细胞。然而，TCR 与 pMHC 的结合如何传递至 CD3 的机制仍不清楚，尽管越来越多的证据表明机械传感和变构都发挥了作用。在这里，我们对识别由 MHC Ⅱ类分子 HLA-DR4 呈递的髓鞘碱性蛋白自身肽的人类自身免疫 TCR（MS2-3C8）进行了 NMR 分析。我们观察到 MS2-3C8 中 pMHC 诱导的 NMR 信号扰动，表明对 TCR β 链构象和动力学的长程影响。我们的结果表明，除了 pMHC 接触残基的 NMR 共振预期变化外，扰动还扩展到 Vβ/Vα、Vβ/Cβ 和 Cβ/Cα 界面区域。此外，长程扰动的模式与先前在两种 MHC Ⅰ类限制性 TCR 的β 链中检测到的模式相似，从而揭示了三种不相关 TCR 之间的共同变构途径。分子动力学（MD）模拟预测了类似的 pMHC 诱导效应。总之，我们的结果表明，pMHC 结合诱导 TCR β 链在代表性 MHC Ⅰ类和Ⅱ类限制性 TCR 中保守位点的长程变构变化，并且这些位点可能在信号传递信息中发挥作用。
