Peptide-MHC Binding Reveals Conserved Allosteric Sites in MHC Class I- and Class II-Restricted T Cell Receptors (TCRs).
Peptide-MHC Binding Reveals Conserved Allosteric Sites in MHC Class I- and Class II-Restricted T Cell Receptors (TCRs).
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DOI：
10.1016/j.jmb.2020.10.031
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发表时间：
2020-12-04
影响因子：
5.6
通讯作者：
Orban J
中科院分区：
文献类型：
--
作者：
He Y;Agnihotri P;Rangarajan S;Chen Y;Kerzic MC;Ma B;Nussinov R;Mariuzza RA;Orban J
T细胞对于保护免受病原体和癌症的适应性免疫反应至关重要。T细胞受体（TCR）-CD 3复合物包含与三个不变的CD 3二聚体非共价缔合的不同αβ TCR异源二聚体。TCR负责识别与MHC分子（pMHC）结合的抗原肽，而CD 3二聚体将激活信号传递给T细胞。然而，TCR通过pMHC参与传递到CD 3的机制仍然是神秘的，尽管有越来越多的证据表明机械感应和变构都发挥了作用。在这里，我们进行了NMR分析的人自身免疫TCR（MS 2 - 3C 8），识别的自我肽从髓鞘碱性蛋白提出的MHC II类分子HLA-DR 4。我们在MS 2 - 3C 8中观察到pMHC诱导的NMR信号扰动，这表明对TCR β链构象和动力学的长程影响。我们的结果表明，除了预期的pMHC接触残基的NMR共振变化外，扰动还延伸到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）模拟预测类似的pMHC诱导的效果。综上所述，我们的结果表明，pMHC结合诱导TCR β链中代表性MHC I类和II类限制性TCR的保守位点的长程变构变化，并且这些位点可能在信号传导信息中发挥作用。
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.
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影响因子：
7.3
作者：
Brazin KN;Mallis RJ;Das DK;Feng Y;Hwang W;Wang JH;Wagner G;Lang MJ;Reinherz EL
通讯作者：
Reinherz EL
影响因子：
30.5
作者：
Chang VT;Fernandes RA;Ganzinger KA;Lee SF;Siebold C;McColl J;Jönsson P;Palayret M;Harlos K;Coles CH;Jones EY;Lui Y;Huang E;Gilbert RJC;Klenerman D;Aricescu AR;Davis SJ
通讯作者：
Davis SJ
影响因子：
7.3
作者：
Natarajan K;Jiang J;May NA;Mage MG;Boyd LF;McShan AC;Sgourakis NG;Bax A;Margulies DH
通讯作者：
Margulies DH
影响因子：
4.4
作者：
Hawse, William F.;Champion, Matthew M.;Baker, Brian M.
通讯作者：
Baker, Brian M.
影响因子：
4.8
作者：
Kim, Sun Taek;Takeuchi, Koh;Reinherz, Ellis L.
通讯作者：
Reinherz, Ellis L.