The Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia.
Nature. 2010 Oct 14;467(7317):844-8. doi: 10.1038/nature09448.
The pre-T-cell antigen receptor (pre-TCR), expressed by immature thymocytes, has a pivotal role in early T-cell development, including TCR β-selection, survival and proliferation of CD4(-)CD8(-) double-negative thymocytes, and subsequent αβ T-cell lineage differentiation. Whereas αβTCR ligation by the peptide-loaded major histocompatibility complex initiates T-cell signalling, pre-TCR-induced signalling occurs by means of a ligand-independent dimerization event. The pre-TCR comprises an invariant α-chain (pre-Tα) that pairs with any TCR β-chain (TCRβ) following successful TCR β-gene rearrangement. Here we provide the basis of pre-Tα-TCRβ assembly and pre-TCR dimerization. The pre-Tα chain comprised a single immunoglobulin-like domain that is structurally distinct from the constant (C) domain of the TCR α-chain; nevertheless, the mode of association between pre-Tα and TCRβ mirrored that mediated by the Cα-Cβ domains of the αβTCR. The pre-TCR had a propensity to dimerize in solution, and the molecular envelope of the pre-TCR dimer correlated well with the observed head-to-tail pre-TCR dimer. This mode of pre-TCR dimerization enabled the pre-Tα domain to interact with the variable (V) β domain through residues that are highly conserved across the Vβ and joining (J) β gene families, thus mimicking the interactions at the core of the αβTCR's Vα-Vβ interface. Disruption of this pre-Tα-Vβ dimer interface abrogated pre-TCR dimerization in solution and impaired pre-TCR expression on the cell surface. Accordingly, we provide a mechanism of pre-TCR self-association that allows the pre-Tα chain to simultaneously 'sample' the correct folding of both the V and C domains of any TCR β-chain, regardless of its ultimate specificity, which represents a critical checkpoint in T-cell development. This unusual dual-chaperone-like sensing function of pre-Tα represents a unique mechanism in nature whereby developmental quality control regulates the expression and signalling of an integral membrane receptor complex.
未成熟 T 细胞表达的前 T 细胞抗原受体（pre-TCR）在前 T 细胞发育中具有关键作用，包括 TCRβ 选择、CD4(-)CD8(-)双阴性胸腺细胞的存活和增殖，以及随后的αβT 细胞谱系分化。虽然αβTCR 通过与肽负载的主要组织相容性复合物的结合引发 T 细胞信号转导，但 pre-TCR 诱导的信号转导是通过配体非依赖性二聚化事件发生的。pre-TCR 由不变的α链（pre-Tα）组成，该α链与成功 TCRβ 基因重排后的任何 TCRβ 链（TCRβ）配对。在这里，我们提供 pre-Tα-TCRβ 组装和 pre-TCR 二聚化的基础。pre-Tα 链包含一个单一的免疫球蛋白样结构域，该结构域在结构上与 TCRα 链的恒定（C）结构域不同；然而，pre-Tα 与 TCRβ 之间的结合方式与αβTCR 的 Cα-Cβ 结构域介导的方式相似。pre-TCR 易于在溶液中二聚化，并且 pre-TCR 二聚体的分子包络与观察到的头尾相接的 pre-TCR 二聚体非常吻合。这种 pre-TCR 二聚化方式使 pre-Tα 结构域能够通过高度保守的 Vβ 和连接（J）β 基因家族中的残基与 Vβ 结构域相互作用，从而模拟了αβTCR 的 Vα-Vβ 界面核心的相互作用。破坏这个 pre-Tα-Vβ 二聚体界面会破坏溶液中的 pre-TCR 二聚化，并损害细胞表面上的 pre-TCR 表达。因此，我们提供了一种 pre-TCR 自组装的机制，该机制允许 pre-Tα 链同时“采样”任何 TCRβ 链的 V 和 C 结构域的正确折叠，无论其最终特异性如何，这是 T 细胞发育中的一个关键检查点。pre-Tα 的这种不寻常的双重伴侣样感应功能代表了一种独特的机制，即发育质量控制调节完整膜受体复合物的表达和信号转导。
