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Allosteric activation of T-cell antigen receptor signalling by quaternary structure relaxation
bioRxiv - Immunology Pub Date : 2021-01-18 , DOI: 10.1101/2020.12.02.407882
Anna-Lisa Lanz , Giulia Masi , Nicla Porciello , André Cohnen , Deborah Cipria , Dheeraj Prakaash , Štefan Bálint , Roberto Raggiaschi , Donatella Galgano , David K. Cole , Marco Lepore , Omer Dushek , Michael L. Dustin , Mark S. P. Sansom , Antreas C. Kalli , Oreste Acuto

The mechanism of T cell antigen receptor (TCR-CD3) signalling remains elusive. Here, we identified mutations in the transmembrane region of TCRβ or CD3ζ that augmented pMHC-induced signalling, not explicable by enhanced ligand binding, lateral diffusion, clustering or co-receptor function. Using a novel biochemical assay and molecular dynamics simulation, we demonstrated that the gain-of-function mutations loosened interaction between TCRαβ and CD3ζ. We found that, similar to the activating mutations, pMHC binding reduced TCRαβ cohesion with CD3ζ. This event occurred prior to CD3ζ phosphorylation and at 0 oC. Moreover, we demonstrated that soluble monovalent pMHC alone induced signalling and reduced TCRαβ cohesion with CD3ζ in membrane-bound or solubilised TCR-CD3. Our data provide compelling evidence that pMHC binding suffices to activate allosteric changes propagating from TCRαβ to the CD3 subunits, reconfiguring interchain transmembrane region interactions. These dynamic modifications could change the arrangement of TCR-CD3 boundary lipids to licence CD3ζ phosphorylation and initiate signal propagation.

中文翻译:

通过四级结构弛豫对T细胞抗原受体信号的变构活化

T细胞抗原受体(TCR-CD3)信号转导的机制尚不清楚。在这里,我们确定了TCRβ或CD3ζ跨膜区域中的突变,这些突变增强了pMHC诱导的信号传导,而不能通过增强的配体结合,侧向扩散,聚集或共受体功能来解释。使用新颖的生化分析和分子动力学模拟,我们证明了功能获得性突变使TCRαβ和CD3ζ之间的相互作用松动。我们发现,与激活突变相似,pMHC结合降低了TCRαβ与CD3ζ的内聚力。此事件发生在CD3ζ磷酸化之前和0 oC。此外,我们证明了可溶性单价pMHC单独诱导了信号传导,并降低了膜结合或溶解的TCR-CD3中CD3ζ与TCRαβ的内聚力。我们的数据提供了令人信服的证据,证明pMHC结合足以激活从TCRαβ传播至CD3亚基的变构变化,从而重新构筑链间跨膜区域相互作用。这些动态修饰可以改变TCR-CD3边界脂质的排列,以许可CD3ζ磷酸化并启动信号传播。
更新日期:2021-01-18
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