Computational model of E-cadherin clustering under force
Computational model of E-cadherin clustering under force
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DOI：
10.1016/j.bpj.2021.10.018
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发表时间：
2021-11-16
影响因子：
3.4
通讯作者：
Bidone, Tamara C.
中科院分区：
文献类型：
--
作者：
Chen, Yang;Brasch, Julia;Bidone, Tamara C.
E-钙粘蛋白在细胞间粘附的形成中起关键作用，用于多种生理功能，包括组织发育、修复和稳态。E-cadherins簇的形成涉及E-cadherin胞外结构域之间的细胞外粘附（反式）和侧向（顺式）缔合以及通过与肌动球蛋白细胞骨架的细胞内结合的稳定化。这种结合为粘附提供力，并且是机械转导所需的。然而，细胞骨架力对E-cadherins聚集的确切作用尚不清楚。为了深入了解这种机制，我们开发了一个基于布朗动力学的计算模型。在该模型中，E-钙粘蛋白在结构和功能状态之间转换;它们能够通过反式和顺式相互作用结合和解结合相同和/或相反细胞上的其他E-钙粘蛋白，同时也与肌动球蛋白细胞骨架建立动态联系。我们的研究结果表明，肌动球蛋白力控制E-cadherins在集群中的分数和集群的大小和数量。对于低的力（低于10 pN），大量的小的E-钙粘蛋白簇形成，每个少于5个E-钙粘蛋白。在更高的力下，形成更少但更大的簇的概率增加。这些发现支持了力增强细胞-细胞粘附的观点，这与先前观察到的上皮组织顶端和侧部连接处之间的簇大小差异一致。
E-cadherins play a critical role in the formation of cell-cell adhesions for several physiological functions, including tissue development, repair, and homeostasis. The formation of clusters of E-cadherins involves extracellular adhesive (trans-) and lateral (cis-) associations between E-cadherin ectodomains and stabilization through intracellular binding to the actomyosin cytoskeleton. This binding provides force to the adhesion and is required for mechanotransduction. However, the exact role of cytoskeletal force on the clustering of E-cadherins is not well understood. To gain insights into this mechanism, we developed a computational model based on Brownian dynamics. In the model, E-cadherins transit between structural and functional states; they are able to bind and unbind other E-cadherins on the same and/or opposite cell(s) through trans- and cis-interactions while also creating dynamic links with the actomyosin cytoskeleton. Our results show that actomyosin force governs the fraction of E-cadherins in clusters and the size and number of clusters. For low forces (below 10 pN), a large number of small E-cadherin clusters form with less than five E-cadherins each. At higher forces, the probability of forming fewer but larger clusters increases. These findings support the idea that force reinforces cell-cell adhesions, which is consistent with differences in cluster size previously observed between apical and lateral junctions of epithelial tissues.