T cell receptor-ligand interactions: A conformational preequilibrium or an induced fit
T cell receptor-ligand interactions: A conformational preequilibrium or an induced fit
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DOI：
10.1073/pnas.0402840101
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发表时间：
2004-06-15
影响因子：
11.1
通讯作者：
Pecht, I
中科院分区：
文献类型：
--
作者：
Gakamsky, DM;Luescher, IF;Pecht, I
T细胞受体（TCR）与其配体相互作用的动力学参数已被提出以控制T细胞活化。迄今为止，对获得的动力学数据的分析产生了相互矛盾的见解；在此，我们提出对这个问题的思考。以可溶性TCR （sT1）及其特异性配体SYIPSAEK-(ABA)1的叠氮苯甲酸衍生物（柏氏疟原虫环孢子子蛋白残基252-260）为模型体系，利用表面等离子体共振研究了其与MHC H-2K(d)编码分子（MHCp）的结合和解离。联想时程呈现双相模式。快速和优势相被分配给与主要部分TCR分子的配体结合，而缓慢组分归因于痕量TCR二聚体的存在。在假设可逆的单步反应机制下，快速相的缔合速率常数相对缓慢且明显依赖于温度，从25℃时的7.0 × 10(3)下降到4℃时的1.8 × 10(2) M(-1)s（-1）。因此，我们认为这些观察到的慢速率常数是该过程中未解决的基本步骤的结果。事实上，我们对动力学数据的分析表明，TCR- mhcp相互作用的时间过程符合两种不同但密切相关的机制，其中两个未结合的TCR构象的诱导拟合或预平衡是可操作的。这些机制可能为报道的TCR的构象灵活性及其不寻常的配体识别特性提供了基本原理，这些特性结合了高特异性和相当大的交叉反应性。
Kinetic parameters of T cell receptor (TCR) interactions with its ligand have been proposed to control T cell activation. Analysis of kinetic data obtained has so far produced conflicting insights; here, we offer a consideration of this problem. As a model system, association and dissociation of a soluble TCR (sT1) and its specific ligand, an azidobenzoic acid derivative of the peptide SYIPSAEK-(ABA)1 (residues 252-260 from Plasmodium berghei circumsporozoite protein), bound to class 1 MHC H-2K(d)-encoded molecule (MHCp) were studied by surface plasmon resonance. The association time courses exhibited biphasic patterns. The fast and dominant phase was assigned to ligand association with the major fraction of TCR molecules, whereas the slow component was attributed to the presence of traces of TCR dimers. The association rate constant derived for the fast phase, assuming a reversible, single-step reaction mechanism, was relatively slow and markedly temperature-dependent, decreasing from 7.0 x 10(3) at 25degreesC to 1.8 x 10(2) M(-1.)s(-1) at 4degreesC. Hence, it is suggested that these observed slow rate constants are the result of unresolved elementary steps of the process. indeed, our analysis of the kinetic data shows that the time courses of TCR-MHCp interaction fit well to two different, yet closely related mechanisms, where an induced fit or a preequilibrium of two unbound TCR conformers are operational. These mechanisms may provide a rationale for the reported conformational flexibility of the TCR and its unusual ligand recognition properties, which combine high specificity with considerable cross-reactivity.