TCR-CD3复合物跨膜区自组装的分子机制

The Molecular Mechanism of TCR-CD3 Complex Self-assembly

目的T细胞受体-共受体复合物(TCR-CD3)在适应性免疫应答中起着重要作用,其亚基间的相互作用一直是研究热点。由于传统实验的局限性,对于跨膜蛋白TCR-CD3复合物的研究不能深入到微观层面。方法利用分子动力学模拟方法(包括粗粒化模拟、拉伸动力学、全原子模拟)分析TCR-CD3复合物的自组装机制。结果通过粗粒化模拟(CGMD)发现,TCR-CD3复合物在组装过程中存在着αβ依次结合δε’、γε、ζζ’的组装顺序,并阐述了α;突变会降低α;与δε’的相互作用。结论本文论证了仅存在TCR-CD3复合物的跨膜区不足以介导TCR-CD3复合物亚基间的特异性相互作用。拉伸动力学(SMD)和全原子模拟(AAMD)的结果说明,ζζ’与TCR-CD3其余部分之间的胞外区相互作用强于跨膜区,同时ζζ’的缺失对αβδε’γε的稳定性影响最小,而δε’的缺失对αβγεζζ’的稳定性影响最大。

Objective The T cell receptor-co-receptor complex(TCR-CD3)plays an important role in the adaptive immune response,and the interaction between its subunits has always been a research hotspot.Due to the limitations of traditional experiments,the study of transmembrane protein TCR-CD3 complexes cannot go deep into the microscopic level.Methods Therefore,we used molecular dynamics simulation methods to analyze the self-assembly mechanism of TCR-CD3 complexes.Results Through coarse-grained simulation(CGMD),we found that the TCR-CD3 complex has an assembly sequence in whichαβsequentially bindsδε’,γε,andζζ’during the assembly process,and explained that theα;mutation reduces the interaction betweenα;andδε’.Conclusion We demonstrated that only the transmembrane region of the TCR-CD3 complex is not sufficient to mediate the specific interaction between the subunits of the TCR-CD3 complex.The results of steered dynamics(SMD)and all-atom simulation(AAMD)indicate that the extracellular interaction betweenζζ’and the rest of TCR-CD3 is stronger than the transmembrane region.The absence ofζζ’makes the stability ofαβδε’γεlittle change,while the absence ofδε’greatly reduces the stability ofαβγεζζ’.