A computational study for understanding the impact of p120-catenin on the cis-dimerization of cadherin.

IF 5.3 2区 生物学 Q2 CELL BIOLOGY
Zhaoqian Su, Vinh H Vu, Deborah E Leckband, Yinghao Wu
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Abstract

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.

了解p120连环蛋白对钙粘蛋白顺式二聚作用影响的计算研究。
跨膜信号转导的原型是细胞表面受体与其配体的细胞外结合诱导细胞内信号级联。然而,人们对相反方向的过程知之甚少,这种过程被称为由内而外的信号传导。最近的研究表明,它在调节许多细胞表面受体的功能方面发挥着比我们过去想象的更重要的作用。特别是,在钙粘蛋白介导的细胞粘附中,最近的实验表明支架蛋白p120连环蛋白的细胞内结合可以促进钙粘蛋白的细胞外聚集并改变其粘附功能。然而,其根本机制尚不清楚。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,我们发现钙粘蛋白胞外区的构象动力学可以通过p120连环蛋白的细胞内结合来改变。更有趣的是,通过将所有原子模拟结果整合到粗粒度随机采样中,我们发现由p120连环蛋白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钙粘蛋白之间横向相互作用的概率。这些结果表明,p120连环蛋白可以通过两种机制变构调节钙粘蛋白的顺式二聚。首先,p120连环蛋白控制钙粘蛋白的细胞外构象动力学。其次,p120连环蛋白寡聚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粘附中由内而外的信号传导提供了机制基础,而该计算框架通常可以应用于其他跨膜信号转导系统。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
9.60
自引率
1.80%
发文量
1383
期刊介绍: The Journal of Molecular Cell Biology ( JMCB ) is a full open access, peer-reviewed online journal interested in inter-disciplinary studies at the cross-sections between molecular and cell biology as well as other disciplines of life sciences. The broad scope of JMCB reflects the merging of these life science disciplines such as stem cell research, signaling, genetics, epigenetics, genomics, development, immunology, cancer biology, molecular pathogenesis, neuroscience, and systems biology. The journal will publish primary research papers with findings of unusual significance and broad scientific interest. Review articles, letters and commentary on timely issues are also welcome. JMCB features an outstanding Editorial Board, which will serve as scientific advisors to the journal and provide strategic guidance for the development of the journal. By selecting only the best papers for publication, JMCB will provide a first rate publishing forum for scientists all over the world.
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