Biocenter Oulu and Department of Biochemistry, University of Oulu, P.O. Box 3000, Oulu FI-90014, Finland.
J Am Chem Soc. 2013 Feb 13;135(6):2188-97. doi: 10.1021/ja308413e. Epub 2013 Feb 1.
The T cell receptor (TCR) together with accessory cluster of differentiation 3 (CD3) molecules (TCR-CD3 complex) is a key component in the primary function of T cells. The nature of association of the transmembrane domains is of central importance to the assembly of the complex and is largely unknown. Using multiscale molecular modeling and simulations, we have investigated the structure and assembly of the TCRα-CD3ε-CD3δ transmembrane domains both in membrane and in micelle environments. We demonstrate that in a membrane environment the transmembrane basic residue of the TCR closely interacts with both of the transmembrane acidic residues of the CD3 dimer. In contrast, in a micelle the basic residue interacts with only one of the acidic residues. Simulations of a recent micellar nuclear magnetic resonance structure of the natural killer (NK) cell-activating NKG2C-DAP12-DAP12 trimer in a membrane further indicate that the environment significantly affects the way these trimers associate. Since the currently accepted model for transmembrane association is entirely based on a micellar structure, we propose a revised model for the association of transmembrane domains of the activating immune receptors in a membrane environment.
T 细胞受体 (TCR) 与辅助分化簇 3 (CD3) 分子簇 (TCR-CD3 复合物) 一起是 T 细胞主要功能的关键组成部分。跨膜结构域的缔合性质对于复合物的组装至关重要，但在很大程度上尚不清楚。我们使用多尺度分子建模和模拟研究了 TCRα-CD3ε-CD3δ 跨膜结构域在膜和胶束环境中的结构和组装。我们证明，在膜环境中，TCR 的跨膜碱性残基与 CD3 二聚体的两个跨膜酸性残基都密切相互作用。相比之下，在胶束中，碱性残基仅与一个酸性残基相互作用。对最近在膜中进行的自然杀伤 (NK) 细胞激活 NKG2C-DAP12-DAP12 三聚体的胶束核磁共振结构的模拟进一步表明，环境显著影响这些三聚体的缔合方式。由于目前接受的跨膜缔合模型完全基于胶束结构，我们提出了一种在膜环境中激活免疫受体的跨膜结构域缔合的修正模型。
