Chen Jiawen, Newhall Jillian, Xie Zhong-Ru, Leckband Deborah, Wu Yinghao
Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, New York.
Department of Chemistry, University of Illinois Urbana-Champaign, Urbana, Illinois.
Biophys J. 2016 Oct 4;111(7):1507-1518. doi: 10.1016/j.bpj.2016.08.038.
Cadherin is a cell-surface transmembrane receptor that mediates calcium-dependent cell-cell adhesion and is a major component of adhesive junctions. The formation of intercellular adhesive junctions is initiated by trans binding between cadherins on adjacent cells, which is followed by the clustering of cadherins via the formation of cis interactions between cadherins on the same cell membranes. Moreover, classical cadherins have multiple glycosylation sites along their extracellular regions. It was found that aberrant glycosylation affects the adhesive function of cadherins and correlates with metastatic phenotypes of several cancers. However, a mechanistic understanding of cadherin clustering during cell adhesion and the role of glycosylation in this process is still lacking. Here, we designed a kinetic model that includes multistep reaction pathways for cadherin clustering. We further applied a diffusion-reaction algorithm to numerically simulate the clustering process using a recently developed coarse-grained model. Using experimentally measured rates of trans binding between soluble E-cadherin extracellular domains, we conducted simulations of cadherin-mediated cell-cell binding kinetics, and the results are quantitatively comparable to experimental data from micropipette experiments. In addition, we show that incorporating cadherin clustering via cis interactions further increases intercellular binding. Interestingly, a two-phase kinetic profile was derived under the assumption that glycosylation regulates the kinetic rates of cis interactions. This two-phase profile is qualitatively consistent with experimental results from micropipette measurements. Therefore, our computational studies provide new, to our knowledge, insights into the molecular mechanism of cadherin-based cell adhesion.
钙黏蛋白是一种细胞表面跨膜受体，介导钙依赖性细胞间黏附，是黏附连接的主要成分。细胞间黏附连接的形成始于相邻细胞上钙黏蛋白之间的反式结合，随后通过同一细胞膜上钙黏蛋白之间形成顺式相互作用使钙黏蛋白聚集。此外，经典钙黏蛋白在其细胞外区域有多个糖基化位点。研究发现，异常糖基化会影响钙黏蛋白的黏附功能，并与几种癌症的转移表型相关。然而，目前仍缺乏对细胞黏附过程中钙黏蛋白聚集机制以及糖基化在此过程中作用的理解。在此，我们设计了一个动力学模型，其中包括钙黏蛋白聚集的多步反应途径。我们进一步应用扩散反应算法，使用最近开发的粗粒度模型对聚集过程进行数值模拟。利用实验测量的可溶性E-钙黏蛋白细胞外结构域之间反式结合的速率，我们对钙黏蛋白介导的细胞间结合动力学进行了模拟，结果在定量上与微量移液器实验的实验数据相当。此外，我们表明通过顺式相互作用纳入钙黏蛋白聚集会进一步增加细胞间结合。有趣的是，在糖基化调节顺式相互作用动力学速率的假设下得出了两相动力学曲线。这一两相曲线在定性上与微量移液器测量的实验结果一致。因此，据我们所知，我们的计算研究为基于钙黏蛋白的细胞黏附分子机制提供了新的见解。
