Computational simulations of TNF receptor oligomerization on plasma membrane.
Computational simulations of TNF receptor oligomerization on plasma membrane.
复制标题
质膜上 TNF 受体寡聚化的计算模拟。
作者：
Su,Zhaoqian;Wu,Yinghao
肿瘤坏死因子(TNF)及其相应受体(TNFR)之间的相互作用在炎症反应中起着关键作用。在与配体结合后，发现TNFR受体在细胞表面形成寡聚体。然而，齐聚的潜在机制还不完全清楚。为了解决这一问题，将分子动力学(MD)模拟应用于肿瘤坏死因子受体-1(TNFR-1)与其配体肿瘤坏死因子-α之间的络合物作为实验系统。在全原子(AA)和粗颗粒(CG)水平上的模拟都得到了相似的结果，即TnFR1胞外区在质膜上可以发生较大的波动，而TnFR1TM-α复合体的动力学受到更多的限制。利用马提尼力场的CG模型，我们能够模拟包含多个α-TnFR1复合体的体系，时间尺度为微秒级。我们发现，在CG模拟结束时，通过受体之间的横向相互作用，复合体可以在质膜上聚集成低聚物。我们认为，这种空间组织对于属于肿瘤坏死因子超家族的配体的信号转导效率是必不可少的。我们进一步证明，两个复合体的聚集是由TNFR1受体的N-末端结构域之间的结合启动的。有趣的是，在先前的X射线结晶学实验中，已经观察到两个肿瘤坏死因子受体的N-末端区域之间的界面。因此，我们提供了支持证据，即顺式界面在触发受体齐聚中具有重要的功能。综上所述，我们的研究为理解肿瘤坏死因子信号转导的分子机制提供了新的思路。
The interactions between tumor necrosis factors (TNFs) and their corresponding receptors (TNFRs) play a pivotal role in inflammatory responses. Upon ligand binding, TNFR receptors were found to form oligomers on cell surfaces. However, the underlying mechanism of oligomerization is not fully understood. In order to tackle this problem, molecular dynamics (MD) simulations have been applied to the complex between TNF receptor‐1 (TNFR1) and its ligand TNF‐α as a specific test system. The simulations on both all‐atom (AA) and coarse‐grained (CG) levels achieved the similar results that the extracellular domains of TNFR1 can undergo large fluctuations on plasma membrane, while the dynamics of TNFα‐TNFR1 complex is much more constrained. Using the CG model with the Martini force field, we are able to simulate the systems that contain multiple TNFα‐TNFR1 complexes with the timescale of microseconds. We found that complexes can aggregate into oligomers on the plasma membrane through the lateral interactions between receptors at the end of the CG simulations. We suggest that this spatial organization is essential to the efficiency of signal transduction for ligands that belong to the TNF superfamily. We further show that the aggregation of two complexes is initiated by the association between the N‐terminal domains of TNFR1 receptors. Interestingly, thecis‐interfaces between N‐terminal regions of two TNF receptors have been observed in the previous X‐ray crystallographic experiment. Therefore, we provide supportive evidence thatcis‐interface is of functional importance in triggering the receptor oligomerization. Taken together, our study brings insights to understand the molecular mechanism of TNF signaling.