Department of Systems and Computational Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Department of Biochemistry and University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA.
J Mol Cell Biol. 2024 Apr 4;15(9). doi: 10.1093/jmcb/mjad055.
A prototype of cross-membrane signal transduction is that extracellular binding of cell surface receptors to their ligands induces intracellular signalling cascades. However, much less is known about the process in the opposite direction, called inside-out signalling. Recent studies show that it plays a more important role in regulating the functions of many cell surface receptors than we used to think. In particular, in cadherin-mediated cell adhesion, recent experiments indicate that intracellular binding of the scaffold protein p120-catenin (p120ctn) can promote extracellular clustering of cadherin and alter its adhesive function. The underlying mechanism, however, is not well understood. To explore possible mechanisms, we designed a new multiscale simulation procedure. Using all-atom molecular dynamics simulations, we found that the conformational dynamics of the cadherin extracellular region can be altered by the intracellular binding of p120ctn. More intriguingly, by integrating all-atom simulation results into coarse-grained random sampling, we showed that the altered conformational dynamics of cadherin caused by the binding of p120ctn can increase the probability of lateral interactions between cadherins on the cell surface. These results suggest that p120ctn could allosterically regulate the cis-dimerization of cadherin through two mechanisms. First, p120ctn controls the extracellular conformational dynamics of cadherin. Second, p120ctn oligomerization can further promote cadherin clustering. Therefore, our study provides a mechanistic foundation for the inside-out signalling in cadherin-mediated cell adhesion, while the computational framework can be generally applied to other cross-membrane signal transduction systems.
跨膜信号转导的一个原型是，细胞表面受体与配体的细胞外结合诱导细胞内信号级联。然而，关于相反方向的过程，即所谓的内向外信号转导，我们知之甚少。最近的研究表明，它在调节许多细胞表面受体的功能方面起着比我们以前认为的更为重要的作用。特别是在钙粘蛋白介导的细胞黏附中，最近的实验表明，支架蛋白 p120 连环蛋白（p120ctn）的细胞内结合可以促进钙粘蛋白的细胞外聚集并改变其黏附功能。然而，其潜在的机制尚不清楚。为了探索可能的机制，我们设计了一种新的多尺度模拟程序。使用全原子分子动力学模拟，我们发现 p120ctn 的细胞内结合可以改变钙粘蛋白细胞外区域的构象动力学。更有趣的是，通过将全原子模拟结果整合到粗粒随机采样中，我们表明 p120ctn 结合引起的钙粘蛋白构象动力学的改变可以增加细胞表面上钙粘蛋白之间侧向相互作用的概率。这些结果表明，p120ctn 可以通过两种机制变构调节钙粘蛋白的顺式二聚化。首先，p120ctn 控制钙粘蛋白的细胞外构象动力学。其次，p120ctn 寡聚化可以进一步促进钙粘蛋白的聚集。因此，我们的研究为钙粘蛋白介导的细胞黏附中的内向外信号转导提供了一个机制基础，而计算框架可以普遍应用于其他跨膜信号转导系统。
