PreTCRs use horizontal docking geometry The T cell receptor (TCR) recognizes peptide-bound major histocompatibility complex molecules (pMHCs) and consists of an α chain in association with a β chain. Both chains have hypervariable complementarity-determining regions (CDRs) that inform whether a particular TCR can recognize a given pMHC. To successfully graduate from the thymus, aspiring αβT cells must generate a functional TCR. During one early checkpoint in this process, the β chain is first paired with a preTβ chain to form the preTCR. Li et al. used x-ray crystallography to visualize how preTCRs recognize pMHCs. They report that the CDR3 loop of the preTCR β chain contacts the pMHC with a distinctive lateral topography. This is in contrast to the established binding modality of mature TCRs, whereby all three CDR loops on both α and β chains bind in a vertical orientation. These complexes help solve the mystery of how only functionally rearranged β chains using competent CDR3 loops can properly engage with pMHC at the preTCR stage. Science, this issue p. 181 A dynamic preTCR binding orientation fosters major histocompatibility complex recognition and thymocyte development. Self-discrimination, a critical but ill-defined molecular process programmed during thymocyte development, requires myriad pre–T cell receptors (preTCRs) and αβTCRs. Using x-ray crystallography, we show how a preTCR applies the concave β-sheet surface of its single variable domain (Vβ) to “horizontally” grab the protruding MHC α2-helix. By contrast, αβTCRs purpose all six complementarity-determining region (CDR) loops of their paired VαVβ module to recognize peptides bound to major histocompatibility complex molecules (pMHCs) in “vertical” head-to-head binding. The preTCR topological fit ensures that CDR3β reaches the peptide’s featured C-terminal segment for pMHC sampling, establishing the subsequent αβTCR canonical docking mode. “Horizontal” docking precludes germline CDR1β- and CDR2β-MHC binding to broaden β-chain repertoire diversification before αβTCR-mediated selection refinement. Thus, one subunit successively attunes the recognition logic of related multicomponent receptors.

中文翻译：

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前 T 细胞受体在胸腺细胞 β 选择过程中拓扑采样自配体


PreTCR 使用水平对接几何结构 T 细胞受体 (TCR) 识别肽结合的主要组织相容性复合体分子 (pMHC)，并由与 β 链结合的 α 链组成。两条链都具有高变互补决定区 (CDR)，可告知特定 TCR 是否可以识别给定的 pMHC。为了成功地从胸腺中毕业，有抱负的 αβT 细胞必须产生功能性 TCR。在此过程的一个早期检查点中，β 链首先与 preTβ 链配对形成 preTCR。李等人。使用 X 射线晶体学来可视化 preTCR 如何识别 pMHC。他们报告说，preTCR β 链的 CDR3 环以独特的横向拓扑与 pMHC 接触。这与成熟 TCR 的既定结合方式相反，即 α 链和 β 链上的所有三个 CDR 环均以垂直方向结合。这些复合物有助于解开这样一个谜团：只有使用有能力的 CDR3 环进行功能性重排的 β 链才能在 preTCR 阶段正确地与 pMHC 结合。科学，本期第 14 页。 181 动态 preTCR 结合方向促进主要组织相容性复合物识别和胸腺细胞发育。自我歧视是胸腺细胞发育过程中一个关键但不明确的分子过程，需要无数的前 T 细胞受体 (preTCR) 和 αβTCR。使用 X 射线晶体学，我们展示了 preTCR 如何应用其单可变结构域 (Vβ) 的凹 β 片层表面来“水平”抓住突出的 MHC α2 螺旋。相比之下，αβTCR 的目的是其配对的 VαVβ 模块的所有六个互补决定区 (CDR) 环来识别以“垂直”头对头结合方式与主要组织相容性复合体分子 (pMHC) 结合的肽。 preTCR 拓扑拟合确保 CDR3β 到达肽的特征 C 末端片段以进行 pMHC 采样，建立后续的 αβTCR 规范对接模式。 “水平”对接排除了种系 CDR1β- 和 CDR2β-MHC 结合，以在 αβTCR 介导的选择细化之前扩大 β 链库多样化。因此，一个亚基连续调节相关多组分受体的识别逻辑。