Structural Features of the αβTCR Mechanotransduction Apparatus That Promote pMHC Discrimination.
Structural Features of the αβTCR Mechanotransduction Apparatus That Promote pMHC Discrimination.
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DOI：
10.3389/fimmu.2015.00441
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发表时间：
2015
影响因子：
7.3
通讯作者：
Reinherz EL
中科院分区：
文献类型：
--
作者：
Brazin KN;Mallis RJ;Das DK;Feng Y;Hwang W;Wang JH;Wagner G;Lang MJ;Reinherz EL
最近发现αβTCR作为机械感受器起作用。也就是说，它利用在免疫监视期间和在免疫突触处产生的机械能来驱动通过特异性外源肽-MHC复合物（pMHC）连接后的生化信号传导。在这里，我们审查的结构特征，优化这种跨膜（TM）受体的机械转导。特异性的适应包括（1）位于Vβ和Cβ结构域之间的CβFG环区，其变构地门控动态T细胞受体（TCR）-pMHC键的形成和寿命;（2）αβTCR复合物的异源二聚体CD 3 εγ和CD 3 εδ胞外结构域组分的刚性超β折叠混合物;（3）αβTCR亚单位连接肽连接胞外和TM段，特别是每个CD 3异二聚体亚基中的氧化CxxC基序，其促进通过TM区段和周围脂质的力传递，影响胞质尾构象;和（4）在负荷下伴随pMHC连接的αβTCR复合物的四级变化。生物力如何促进特定的αβ TCR为基础的pMHC的歧视和为什么动态键的形成是动力学校对的主要基础进行了讨论。我们建议，可以利用结构生物学，单分子FRET，光镊和纳米生物学的组合，有见地的原子分子动力学研究的指导下，单个αβTCR亚基组件的分子重排的细节进行分析。最后，我们回顾了最近的数据表明，前TCR复合物采用类似的机械生物学的αβTCR与自身pMHC配体相互作用，影响早期胸腺库选择之前的CD 4 + CD 8+双阳性胸腺细胞发育阶段。
The αβTCR was recently revealed to function as a mechanoreceptor. That is, it leverages mechanical energy generated during immune surveillance and at the immunological synapse to drive biochemical signaling following ligation by a specific foreign peptide–MHC complex (pMHC). Here, we review the structural features that optimize this transmembrane (TM) receptor for mechanotransduction. Specialized adaptations include (1) the CβFG loop region positioned between Vβ and Cβ domains that allosterically gates both dynamic T cell receptor (TCR)–pMHC bond formation and lifetime; (2) the rigid super β-sheet amalgams of heterodimeric CD3εγ and CD3εδ ectodomain components of the αβTCR complex; (3) the αβTCR subunit connecting peptides linking the extracellular and TM segments, particularly the oxidized CxxC motif in each CD3 heterodimeric subunit that facilitates force transfer through the TM segments and surrounding lipid, impacting cytoplasmic tail conformation; and (4) quaternary changes in the αβTCR complex that accompany pMHC ligation under load. How bioforces foster specific αβTCR-based pMHC discrimination and why dynamic bond formation is a primary basis for kinetic proofreading are discussed. We suggest that the details of the molecular rearrangements of individual αβTCR subunit components can be analyzed utilizing a combination of structural biology, single-molecule FRET, optical tweezers, and nanobiology, guided by insightful atomistic molecular dynamic studies. Finally, we review very recent data showing that the pre-TCR complex employs a similar mechanobiology to that of the αβTCR to interact with self-pMHC ligands, impacting early thymic repertoire selection prior to the CD4+CD8+ double positive thymocyte stage of development.