Understanding the functional role of membrane confinements in TNF-mediated signaling by multiscale simulations.
Understanding the functional role of membrane confinements in TNF-mediated signaling by multiscale simulations.
复制标题
DOI：
10.1038/s42003-022-03179-1
复制
发表时间：
2022-03-11
影响因子：
5.9
通讯作者：
Wu Y
中科院分区：
文献类型：
--
作者：
Su Z;Dhusia K;Wu Y
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。 TNFR1 是细胞表面受体，而 TNFα 以可溶性和膜结合形式存在。有趣的是，我们发现TNFR1介导的信号通路的激活优先通过可溶形式的TNFα，这也可以诱导TNFR1在活细胞质膜上聚集。我们开发了一个多尺度模拟框架来比较由可溶性配体和膜结合配体诱导的受体聚类。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，这影响了细胞-细胞界面上配体-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，则只能形成小簇。相比之下，可溶性 TNFα 触发的聚类更加动态，并且聚类的大小在统计上更大。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，考虑到较大的 TNFα-TNFR1 簇更有可能为下游信号通路提供空间平台，我们的研究提供了新的机制见解，说明为什么膜结合形式的 TNFα 不优选 TNFR1 介导的信号通路的激活。苏等。等人。提供了机制见解并证明了膜结合 TNFα 在 TNFR1 受体聚类中的影响。
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. Su et. al. provide mechanistic insights and demonstrate the impact of membrane-bound TNFα in the clustering of TNFR1 receptor clustering.
登录
查看更多内容
影响因子：
2
作者：
Andrews, SS;Bray, D
通讯作者：
Bray, D
影响因子：
5.5
作者：
Halim SA;Sikandari AG;Khan A;Wadood A;Fatmi MQ;Csuk R;Al-Harrasi A
通讯作者：
Al-Harrasi A
影响因子：
4.8
作者：
Chesla, SE;Li, P;Zhu, C
通讯作者：
Zhu, C
影响因子：
30.5
作者：
Brameshuber M;Kellner F;Rossboth BK;Ta H;Alge K;Sevcsik E;Göhring J;Axmann M;Baumgart F;Gascoigne NRJ;Davis SJ;Stockinger H;Schütz GJ;Huppa JB
通讯作者：
Huppa JB
影响因子：
4
作者：
Cairo, Christopher W.
通讯作者：
Cairo, Christopher W.