T cell receptor recognition via cooperative conformational plasticity
T cell receptor recognition via cooperative conformational plasticity
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DOI：
10.1016/j.jmb.2006.08.045
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发表时间：
2006-10-13
影响因子：
5.6
通讯作者：
Baker, Brian M.
中科院分区：
文献类型：
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作者：
Gagnon, Susan J.;Borbulevych, Oleg Y.;Baker, Brian M.
尽管T细胞受体交叉反应性是免疫系统的基本性质，并且与许多自身免疫性病理学有关，但T细胞受体可以识别和响应不同配体的分子机制尚未完全理解。在当前的研究中，我们检查了人T细胞嗜淋巴细胞病毒-1（HTLV-1）Tax特异性T细胞受体（TCR）A6对一组结构不同的半抗原的反应，这些半抗原与Tax 11-19肽偶联，在5位有赖氨酸取代（Tax 5 K，LLFG[K-半抗原]PVYV）。A6 TCR可交叉反应性识别HLA-A*0201呈递的Tax-5 K-4-（3-吲哚基）丁酸（IBA）。Tax 5 K-IBA/HLA-A2游离和与A6复合的晶体结构揭示，结合是由涉及蛋白质-蛋白质界面两侧构象变化的协同构象可塑性机制介导的，包括TCR互补决定区（CDR）环、V α/V β结构域取向和半抗原修饰的肽。我们的研究结果说明了蛋白质动力学在TCR交叉反应性中可以发挥的复杂作用，并强调了T细胞受体对配体的识别可以通过多种复杂的分子机制来实现，这些机制可以在界面中同时发生，而不限于分子模拟和CDR环移位。出版社：Elsevier Ltd
Although T cell receptor cross-reactivity is a fundamental property of the immune system and is implicated in numerous autoimmune pathologies, the molecular mechanisms by which T cell receptors can recognize and respond to diverse ligands are incompletely understood. In the current study we examined the response of the human T cell lymphotropic virus-1 (HTLV-1) Tax-specific T cell receptor (TCR) A6 to a panel of structurally distinct haptens coupled to the Tax 11-19 peptide with a lysine substitution at position 5 (Tax5K, LLFG[K-hapten]PVYV). The A6 TCR could crossreactively recognize one of these haptenated peptides, Tax-5K-4-(3-1ndolyl)* butyric acid (IBA), presented by HLA-A*0201. The crystal structures of Tax5K-IBA/HLA-A2 free and in complex with A6 reveal that binding is mediated by a mechanism of cooperative conformational plasticity involving conformational changes on both sides of the protein-protein interface, including the TCR complementarity determining region (CDR) loops, V alpha/V beta domain orientation, and the hapten-modified peptide. Our findings illustrate the complex role that protein dynamics can play in TCR cross-reactivity and highlight that T cell receptor recognition of ligand can be achieved through diverse and complex molecular mechanisms that can occur simultaneously in the interface, not limited to molecular mimicry and CDR loop shifts. Published by Elsevier Ltd.