Pokutta Sabine, Drees Frauke, Yamada Soichiro, Nelson W James, Weis William I
Department of Structural Biology, D100 Fairchild Science Building, Stanford University School of Medicine, Stanford, CA 94305-5126, U.S.A.
Biochem Soc Trans. 2008 Apr;36(Pt 2):141-7. doi: 10.1042/BST0360141.
Cadherins are transmembrane adhesion molecules that mediate homotypic cell-cell contact. In adherens junctions, the cytoplasmic domain of cadherins is functionally linked to the actin cytoskeleton through a series of proteins known as catenins. E-cadherin binds to beta-catenin, which in turn binds to alpha-catenin to form a ternary complex. alpha-Catenin also binds to actin, and it was assumed previously that alpha-catenin links the cadherin-catenin complex to actin. However, biochemical, structural and live-cell imaging studies of the cadherin-catenin complex and its interaction with actin show that binding of beta-catenin to alpha-catenin prevents the latter from binding to actin. Biochemical and structural data indicate that alpha-catenin acts as an allosteric protein whose conformation and activity changes depending on whether or not it is bound to beta-catenin. Initial contacts between cells occur on dynamic lamellipodia formed by polymerization of branched actin networks, a process controlled by the Arp2/3 (actin-related protein 2/3) complex. alpha-Catenin can suppress the activity of Arp2/3 by competing for actin filaments. These findings lead to a model for adherens junction formation in which clustering of the cadherin-beta-catenin complex recruits high levels of alpha-catenin that can suppress the Arp2/3 complex, leading to cessation of lamellipodial movement and formation of a stable contact. Thus alpha-catenin appears to play a central role in cell-cell contact formation.
钙黏蛋白是介导同型细胞间接触的跨膜黏附分子。在黏着连接中，钙黏蛋白的胞质结构域通过一系列被称为连环蛋白的蛋白质与肌动蛋白细胞骨架功能相连。E-钙黏蛋白与β-连环蛋白结合，β-连环蛋白又与α-连环蛋白结合形成三元复合物。α-连环蛋白也与肌动蛋白结合，之前人们认为α-连环蛋白将钙黏蛋白-连环蛋白复合物与肌动蛋白相连。然而，对钙黏蛋白-连环蛋白复合物及其与肌动蛋白相互作用的生化、结构和活细胞成像研究表明，β-连环蛋白与α-连环蛋白的结合会阻止后者与肌动蛋白结合。生化和结构数据表明，α-连环蛋白是一种变构蛋白，其构象和活性会根据是否与β-连环蛋白结合而发生变化。细胞间的初始接触发生在由分支肌动蛋白网络聚合形成的动态片状伪足上，这一过程由Arp2/3（肌动蛋白相关蛋白2/3）复合物控制。α-连环蛋白可以通过竞争肌动蛋白丝来抑制Arp2/3的活性。这些发现导致了一个关于黏着连接形成的模型，即钙黏蛋白-β-连环蛋白复合物的聚集会募集高水平的α-连环蛋白，后者可以抑制Arp2/3复合物，导致片状伪足运动停止并形成稳定接触。因此，α-连环蛋白似乎在细胞间接触形成中起着核心作用。
