NMR: an essential structural tool for integrative studies of T cell development, pMHC ligand recognition and TCR mechanobiology
NMR: an essential structural tool for integrative studies of T cell development, pMHC ligand recognition and TCR mechanobiology
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DOI：
10.1007/s10858-019-00234-8
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发表时间：
2019-07-01
影响因子：
2.7
通讯作者：
Reinherz, Ellis L.
中科院分区：
文献类型：
--
作者：
Mallis, Robert J.;Brazin, Kristine N.;Reinherz, Ellis L.
使用X射线晶体学、表面等离子体共振（SPR）和等温滴定量热法（ITC）的T细胞结构生物学的早期研究集中于α β T细胞受体（α β TCR）组分结构域及其同源配体（与MHC分子结合的肽，即pMHC）作为静态相互作用配偶体的图片。展望未来，需要将这些数据集与动态技术集成，例如核磁共振、分子动力学（MD）模拟和以光镊（OT）为例的实时单分子（SM）研究。NMR桥接了相关的时间尺度，并提供了在与结合伴侣相互作用之前和期间对α β TCR组分进行全原子动态描述的可能性。SM技术通过将力介导的结合测量引入T细胞功能的范例，在理解T细胞信号传导的非平衡性质方面开辟了前景。在这方面，生物力量的后果T-谱系细胞运动性现在被认为是放置pN-水平的负载上的单一受体pMHC键，影响结构变化和α β T-谱系生物学，包括肽歧视，细胞活化，和发育进程。我们在此讨论必要的NMR技术在阐明前T细胞受体（preTCR），α β TCR发育前体中配体结合的作用，以及NMR，SM和MD数据在推进我们对T细胞发育的理解中的收敛。更广泛地说，我们审查的中心假设，α β TCR是一个机械传感器，突破性的NMR为基础的结构的见解。总的来说，通过NMR、SM和MD的综合使用阐明动态方面将促进对T细胞信号传导机制的基本认识，并为α β TCR和嵌合T细胞（CAR-T）免疫疗法和T细胞疫苗学中的翻译努力提供信息。
Early studies of T cell structural biology using X-ray crystallography, surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) focused on a picture of the alpha beta T cell receptor (alpha beta TCR) component domains and their cognate ligands (peptides bound to MHC molecules, i.e. pMHCs) as static interaction partners. Moving forward requires integrating this corpus of data with dynamic technologies such as NMR, molecular dynamics (MD) simulations and real-time single molecule (SM) studies exemplified by optical tweezers (OT). NMR bridges relevant timescales and provides the potential for an all-atom dynamic description of alpha beta TCR components prior to and during interactions with binding partners. SM techniques have opened up vistas in understanding the non-equilibrium nature of T cell signaling through the introduction of force-mediated binding measurements into the paradigm for T cell function. In this regard, bioforces consequent to T-lineage cell motility are now perceived as placing piconewton (pN)-level loads on single receptor-pMHC bonds to impact structural change and alpha beta T-lineage biology, including peptide discrimination, cellular activation, and developmental progression. We discuss herein essential NMR technologies in illuminating the role of ligand binding in the preT cell receptor (preTCR), the alpha beta TCR developmental precursor, and convergence of NMR, SM and MD data in advancing our comprehension of T cell development. More broadly we review the central hypothesis that the alpha beta TCR is a mechanosensor, fostered by breakthrough NMR-based structural insights. Collectively, elucidating dynamic aspects through the integrative use of NMR, SM, and MD shall advance fundamental appreciation of the mechanism of T cell signaling as well as inform translational efforts in alpha beta TCR and chimeric T cell (CAR-T) immunotherapies and T cell vaccinology.