Department of Systems and Computational Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY, 10461, USA.
Commun Biol. 2022 Mar 11;5(1):228. doi: 10.1038/s42003-022-03179-1.
The interaction between TNFα and TNFR1 is essential in maintaining tissue development and immune responses. While TNFR1 is a cell surface receptor, TNFα exists in both soluble and membrane-bound forms. Interestingly, it was found that the activation of TNFR1-mediated signaling pathways is preferentially through the soluble form of TNFα, which can also induce the clustering of TNFR1 on plasma membrane of living cells. We developed a multiscale simulation framework to compare receptor clustering induced by soluble and membrane-bound ligands. Comparing with the freely diffusive soluble ligands, we hypothesize that the conformational dynamics of membrane-bound ligands are restricted, which affects the clustering of ligand-receptor complexes at cell-cell interfaces. Our simulation revealed that only small clusters can form if TNFα is bound on cell surface. In contrast, the clustering triggered by soluble TNFα is more dynamic, and the size of clusters is statistically larger. We therefore demonstrated the impact of membrane-bound ligand on dynamics of receptor clustering. Moreover, considering that larger TNFα-TNFR1 clusters is more likely to provide spatial platform for downstream signaling pathway, our studies offer new mechanistic insights about why the activation of TNFR1-mediated signaling pathways is not preferred by membrane-bound form of TNFα.
TNFα 和 TNFR1 之间的相互作用对于维持组织发育和免疫反应至关重要。虽然 TNFR1 是一种细胞表面受体，但 TNFα 存在可溶性和膜结合两种形式。有趣的是，研究发现 TNFR1 介导的信号通路的激活更倾向于通过可溶性 TNFα 形式，而后者也可以诱导活细胞质膜上 TNFR1 的聚集。我们开发了一个多尺度模拟框架来比较可溶性和膜结合配体诱导的受体聚集。与自由扩散的可溶性配体相比，我们假设膜结合配体的构象动力学受到限制，这会影响细胞间界面上配体-受体复合物的聚集。我们的模拟表明，如果 TNFα 结合在细胞表面，只有小的簇才能形成。相比之下，可溶性 TNFα 引发的聚类更具动态性，并且聚类的大小在统计学上更大。因此，我们证明了膜结合配体对受体聚类动力学的影响。此外，考虑到更大的 TNFα-TNFR1 簇更有可能为下游信号通路提供空间平台，我们的研究提供了关于为什么 TNFR1 介导的信号通路的激活不被 TNFα 的膜结合形式所偏好的新的机制见解。
