The αβTCR mechanosensor exploits dynamic ectodomain allostery to optimize its ligand recognition site
The αβTCR mechanosensor exploits dynamic ectodomain allostery to optimize its ligand recognition site
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DOI：
10.1073/pnas.2005899117
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发表时间：
2020-09-01
影响因子：
11.1
通讯作者：
Reinherz, Ellis L.
中科院分区：
文献类型：
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作者：
Hwang, Wonmuk;Mallis, Robert J.;Reinherz, Ellis L.
每个α β T细胞受体（TCR）都起着机械传感器的作用。TCR由克隆型TCR α β配体结合异源二聚体和非共价缔合的CD 3信号传导亚基组成。当与配体（由主要组织相容性复合物分子（pMHC）排列的抗原肽）结合时，TCR α β在皮牛顿水平负载下具有更长的键寿命。这种“捕获键”行为的原子机制是未知的。在这里，我们进行分子动力学模拟的TCR α β-pMHC复合物及其变体的生理负荷下，以确定这种机制和任何伴随的TCR α β结构域变构。TCR α β-pMHC界面通过与一系列占位蛋白接触而动态维持，通过含有pMHC结合互补决定区（CDR）环的V α和V β可变结构域之间的相对运动引入一定水平的控制。没有足够的载荷，界面接触是不稳定的，而施加足够的载荷抑制V α-V β运动，稳定界面。第二个水平的控制是由C α和C β恒定结构域，特别是C β及其突出的FG环，产生四个TCR α β结构域之间的错配界面和与pMHC配体。所施加的载荷通过TCR α β分子的变形来增强配合。因此，捕获键共同涉及整个TCR α β构象、域间运动和界面接触动力学。这种多层结构的机械促进微调的细胞响应负荷和pMHC识别。由于生殖系来源的TCR α β胞外域在结构上是保守的，因此所提出的机制可以被普遍采用，以在构成T细胞库的不同α β TCR的免疫监视期间在负荷下操作。
Each alpha beta T cell receptor (TCR) functions as a mechanosensor. The TCR is comprised of a clonotypic TCR alpha beta ligand-binding heterodimer and the noncovalently associated CD3 signaling subunits. When bound by ligand, an antigenic peptide arrayed by a major histocompatibility complex molecule (pMHC), the TCR alpha beta has a longer bond lifetime under piconewton-level loads. The atomistic mechanism of this "catch bond" behavior is unknown. Here, we perform molecular dynamics simulation of a TCR alpha beta-pMHC complex and its variants under physiologic loads to identify this mechanism and any attendant TCR alpha beta domain allostery. The TCR alpha beta-pMHC interface is dynamically maintained by contacts with a spectrum of occupancies, introducing a level of control via relative motion between V alpha and V beta variable domains containing the pMHC-binding complementarity-determining region (CDR) loops. Without adequate load, the interfacial contacts are unstable, whereas applying sufficient load suppresses V alpha-V beta motion, stabilizing the interface. A second level of control is exerted by C alpha and C beta constant domains, especially C beta and its protruding FG-loop, that create mismatching interfaces among the four TCR alpha beta domains and with a pMHC ligand. Applied load enhances fit through deformation of the TCR alpha beta molecule. Thus, the catch bond involves the entire TCR alpha beta conformation, interdomain motion, and interfacial contact dynamics, collectively. This multilayered architecture of the machinery fosters fine-tuning of cellular response to load and pMHC recognition. Since the germline-derived TCR alpha beta ectodomain is structurally conserved, the proposed mechanism can be universally adopted to operate under load during immune surveillance by diverse alpha beta TCRs constituting the T cell repertoire.