Allosteric inhibition of the T cell receptor by a designed membrane ligand.
Allosteric inhibition of the T cell receptor by a designed membrane ligand.
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DOI：
10.7554/elife.82861
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发表时间：
2023-10-05
期刊：
影响因子：
7.7
通讯作者：
Barrera FN
中科院分区：
文献类型：
--
作者：
Ye Y;Morita S;Chang JJ;Buckley PM;Wilhelm KB;DiMaio D;Groves JT;Barrera FN
T细胞受体（TCR）是一种复杂的分子机器，它指导T细胞的激活，使免疫系统能够对抗病原体和癌细胞。尽管经过数十年的研究，TCR活化的分子机制仍然存在争议。其中一个主要的激活假说是变构模型。该模型假设pMHC在胞外区域的结合触发TCR亚基跨膜（TM）区域的动态变化，从而导致细胞质侧的信号传导。我们试图通过为TCR创建TM配体来验证这一假设。之前，我们描述了一种方法来创建一种可溶性肽，能够插入膜并结合到受体酪氨酸激酶EphA2的TM结构域（Alves等人，eLife, 2018）。在这里，我们通过设计TCR的TM配体，表明该方法可推广到复杂的膜受体。我们观察到设计的肽导致T细胞CD3ζ亚基上TCR的Lck磷酸化减少。结果，在这种TCR肽抑制剂（PITCR）的存在下，TCR激活下游的近端信号级联被显著抑制。二异丁烯马来酸（DIBMA）天然纳米片的共定位和共免疫沉淀证实了PITCR能够与TCR结合。AlphaFold-Multimer预测，PITCR结合到TCR的TM区域，在那里它与两个CD3ζ亚基相互作用。我们的研究结果还表明，PITCR破坏了TCR激活时TM束致密性的变构变化，为TCR激活变构模型提供了支持。通过PITCR实现的TCR抑制可能有助于治疗炎症性和自身免疫性疾病，并预防器官移植排斥反应，因为在这些情况下，TCR的异常激活会导致疾病。
The T cell receptor (TCR) is a complex molecular machine that directs the activation of T cells, allowing the immune system to fight pathogens and cancer cells. Despite decades of investigation, the molecular mechanism of TCR activation is still controversial. One of the leading activation hypotheses is the allosteric model. This model posits that binding of pMHC at the extracellular domain triggers a dynamic change in the transmembrane (TM) domain of the TCR subunits, which leads to signaling at the cytoplasmic side. We sought to test this hypothesis by creating a TM ligand for TCR. Previously we described a method to create a soluble peptide capable of inserting into membranes and binding to the TM domain of the receptor tyrosine kinase EphA2 (Alves et al., eLife, 2018). Here, we show that the approach is generalizable to complex membrane receptors, by designing a TM ligand for TCR. We observed that the designed peptide caused a reduction of Lck phosphorylation of TCR at the CD3ζ subunit in T cells. As a result, in the presence of this peptide inhibitor of TCR (PITCR), the proximal signaling cascade downstream of TCR activation was significantly dampened. Co-localization and co-immunoprecipitation in diisobutylene maleic acid (DIBMA) native nanodiscs confirmed that PITCR was able to bind to the TCR. AlphaFold-Multimer predicted that PITCR binds to the TM region of TCR, where it interacts with the two CD3ζ subunits. Our results additionally indicate that PITCR disrupts the allosteric changes in the compactness of the TM bundle that occur upon TCR activation, lending support to the allosteric TCR activation model. The TCR inhibition achieved by PITCR might be useful to treat inflammatory and autoimmune diseases and to prevent organ transplant rejection, as in these conditions aberrant activation of TCR contributes to disease.
影响因子：
2.9
作者：
Smith, Adam W.;Smoligovets, Alexander A.;Groves, Jay T.
通讯作者：
Groves, Jay T.
影响因子：
64.5
作者：
Kuhns MS;Davis MM
通讯作者：
Davis MM