The Cell Adhesion Laboratory, UF Scripps, Jupiter, FL, 33458, USA.
The Skaggs Graduate School, The Scripps Research Institute, Jupiter, FL, 33458, USA.
Commun Biol. 2023 Mar 16;6(1):276. doi: 10.1038/s42003-023-04610-x.
Attachment between cells is crucial for almost all aspects of the life of cells. These inter-cell adhesions are mediated by the binding of transmembrane cadherin receptors of one cell to cadherins of a neighboring cell. Inside the cell, cadherin binds β-catenin, which interacts with α-catenin. The transitioning of cells between migration and adhesion is modulated by α-catenin, which links cell junctions and the plasma membrane to the actin cytoskeleton. At cell junctions, a single β-catenin/α-catenin heterodimer slips along filamentous actin in the direction of cytoskeletal tension which unfolds clustered heterodimers to form catch bonds with F-actin. Outside cell junctions, α-catenin dimerizes and links the plasma membrane to F-actin. Under cytoskeletal tension, α-catenin unfolds and forms an asymmetric catch bond with F-actin. To understand the mechanism of this important α-catenin function, we determined the 2.7 Å cryogenic electron microscopy (cryoEM) structures of filamentous actin alone and bound to human dimeric α-catenin. Our structures provide mechanistic insights into the role of the α-catenin interdomain interactions in directing α-catenin function and suggest a bivalent mechanism. Further, our cryoEM structure of human monomeric α-catenin provides mechanistic insights into α-catenin autoinhibition. Collectively, our structures capture the initial α-catenin interaction with F-actin before the sensing of force, which is a crucial event in cell adhesion and human disease.
细胞间的附着对于细胞生命的几乎所有方面都是至关重要的。这些细胞间的黏附是通过一个细胞的跨膜钙黏蛋白受体与相邻细胞的钙黏蛋白结合介导的。在细胞内，钙黏蛋白与β-连环蛋白结合，β-连环蛋白与α-连环蛋白相互作用。α-连环蛋白调节细胞在迁移和黏附之间的转换，它将细胞连接和质膜与肌动蛋白细胞骨架连接起来。在细胞连接处，单个β-连环蛋白/α-连环蛋白异二聚体沿着丝状肌动蛋白向细胞骨架张力的方向滑动，解开聚集的异二聚体，与 F-肌动蛋白形成捕获键。在细胞连接处之外，α-连环蛋白二聚化并将质膜与 F-肌动蛋白连接。在细胞骨架张力下，α-连环蛋白展开并与 F-肌动蛋白形成不对称的捕获键。为了理解这种重要的α-连环蛋白功能的机制，我们确定了单独的丝状肌动蛋白和与人二聚体α-连环蛋白结合的结构的 2.7 Å 冷冻电子显微镜（cryoEM）结构。我们的结构提供了对α-连环蛋白结构域间相互作用在指导α-连环蛋白功能中的作用的机制见解，并提出了双价机制。此外，我们的人单体α-连环蛋白的 cryoEM 结构提供了对α-连环蛋白自身抑制的机制见解。总之，我们的结构捕获了在力感应之前α-连环蛋白与 F-肌动蛋白的初始相互作用，这是细胞黏附和人类疾病中的一个关键事件。
