Davis-Harrison Rebecca L, Insaidoo Francis K, Baker Brian M
Department of Chemistry and Biochemistry and Walther Cancer Research Center, 251 Nieuwland Science Hall, University of Notre Dame, Notre Dame, Indiana 46556, USA.
Biochemistry. 2007 Feb 20;46(7):1840-50. doi: 10.1021/bi061702p. Epub 2007 Jan 24.
T cell receptor recognition of peptide/MHC has been described as proceeding through a "two-step" process in which the TCR first contacts the MHC molecule prior to formation of the binding transition state using the germline-encoded CDR1 and CDR2 loops. The receptor then contacts the peptide using the hypervariable CDR3 loops as the transition state decays to the bound state. The model subdivides TCR binding into peptide-independent and peptide-dependent steps, demarcated at the binding transition state. Investigating the two-step model, here we show that two TCRs that recognize the same peptide/MHC bury very similar amounts of solvent-accessible surface area in their transition states. However, 1300-1500 A2 of surface area is buried in each, a significant amount suggestive of participation of peptide and associated CDR3 surface. Consistent with this interpretation, analysis of peptide and TCR variants indicates that stabilizing contacts to the peptide are formed within both transition states. These data are incompatible with the original two-step model, as are transition state models built using the principle of minimal frustration commonly employed in the investigation of protein folding and binding transition states. These findings will be useful in further explorations of the nature of TCR binding transition states, as well as ongoing efforts to understand the mechanisms by which T cell receptors recognize the composite peptide/MHC surface.
T细胞受体对肽/MHC的识别被描述为通过一个“两步”过程进行，其中TCR在使用种系编码的CDR1和CDR2环形成结合过渡态之前首先接触MHC分子。然后，随着过渡态衰减到结合态，受体使用高变CDR3环接触肽。该模型将TCR结合细分为肽非依赖和肽依赖步骤，在结合过渡态处划分。在研究两步模型时，我们在此表明，识别相同肽/MHC的两个TCR在其过渡态中掩埋的溶剂可及表面积非常相似。然而，每个TCR掩埋的表面积为1300 - 1500 Ų，这一显著数量表明肽和相关CDR3表面参与其中。与这种解释一致，对肽和TCR变体的分析表明，在两个过渡态中都形成了与肽的稳定接触。这些数据与原始两步模型不兼容，使用蛋白质折叠和结合过渡态研究中常用的最小受挫原理构建的过渡态模型也是如此。这些发现将有助于进一步探索TCR结合过渡态的性质，以及目前为理解T细胞受体识别复合肽/MHC表面的机制所做的努力。
