W. M. Keck Laboratory for Structural Biology, University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, MD 20850, USA.
Proc Natl Acad Sci U S A. 2012 Sep 11;109(37):14960-5. doi: 10.1073/pnas.1207186109. Epub 2012 Aug 28.
The conserved diagonal docking mode observed in structures of T-cell receptors (TCRs) bound to peptide-MHC ligands is believed to reflect coevolution of TCR and MHC genes. This coevolution is supported by the conservation of certain interactions between the germ-line-encoded complementarity-determining region (CDR)1 and CDR2 loops of TCR and MHC. However, the rules governing these interactions are not straightforward, even when the same variable (V) region recognizes the same MHC molecule. Here, we demonstrate that the somatically generated CDR3 loops can markedly alter evolutionarily selected contacts between TCR and MHC ("CDR3 editing"). To understand CDR3 editing at the atomic level, we determined the structure of a human melanoma-specific TCR (G4) bound to the MHC class II molecule HLA-DR1 and an epitope from mutant triose phosphate isomerase (mutTPI). A comparison of the G4-mutTPI-DR1 complex with a complex involving a TCR (E8) that uses the same Vα region to recognize the same mutTPI-DR1 ligand as G4 revealed that CDR1α adopts markedly different conformations in the two TCRs, resulting in an almost entirely different set of contacts with MHC. Based on the structures of unbound G4 and E8, the distinct conformations of CDR1α in these TCRs are not induced by binding to mutTPI-DR1 but result from differences in the length and sequence of CDR3α that are transmitted to CDR1α. The editing of germ-line-encoded TCR-MHC interactions by CDR3 demonstrates that these interactions possess sufficient intrinsic flexibility to accommodate large structural variations in CDR3 and, consequently, in the TCR-binding site.
T 细胞受体 (TCR) 与肽-MHC 配体结合的结构中观察到保守的对角对接模式，据信反映了 TCR 和 MHC 基因的共同进化。这种共同进化得到了 TCR 和 MHC 中胚系编码的互补决定区 (CDR)1 和 CDR2 环之间某些相互作用的保守性的支持。然而，即使相同的可变 (V) 区识别相同的 MHC 分子，这些相互作用的规则也不是直截了当的。在这里，我们证明体细胞产生的 CDR3 环可以显著改变 TCR 和 MHC 之间进化选择的接触（“CDR3 编辑”）。为了在原子水平上理解 CDR3 编辑，我们确定了与人黑色素瘤特异性 TCR (G4) 结合的结构，该 TCR 与 MHC 类 II 分子 HLA-DR1 和突变三磷酸甘油醛异构酶 (mutTPI) 的表位结合。将 G4-mutTPI-DR1 复合物与涉及使用相同 Vα 区识别 G4 作为相同 mutTPI-DR1 配体的 TCR (E8) 的复合物进行比较，结果表明 CDR1α 在这两个 TCR 中采用了截然不同的构象，导致与 MHC 的接触几乎完全不同。基于未结合的 G4 和 E8 的结构，这些 TCR 中 CDR1α 的不同构象不是由与 mutTPI-DR1 结合引起的，而是由于 CDR3α 的长度和序列的差异引起的，这些差异传递到 CDR1α。CDR3 对 TCR-MHC 相互作用的胚系编辑表明，这些相互作用具有足够的内在灵活性，可以适应 CDR3 以及 TCR 结合位点的大结构变化。
