Mechanism of the cadherin-catenin F-actin catch bond interaction

Abstract

Mechanotransduction at cell-cell adhesions is crucial for the structural integrity, organization, and morphogenesis of epithelia. At cell-cell junctions, ternary E-cadherin/β-catenin/αE-catenin complexes sense and transmit mechanical load by binding to F-actin. The interaction with F-actin, described as a two-state catch bond, is weak in solution but is strengthened by applied force due to force-dependent transitions between weak and strong actin-binding states. Here, we provide direct evidence from optical trapping experiments that the catch bond property principally resides in the αE-catenin actin-binding domain (ABD). Consistent with our previously proposed model, deletion of the first helix of the five-helix ABD bundle enables stable interactions with F-actin under minimal load that are well-described by a single-state slip bond, even when αE-catenin is complexed with β-catenin and E-cadherin. Our data argue for a conserved catch bond mechanism for adhesion proteins with structurally similar ABDs. We also demonstrate that a stably bound ABD strengthens load-dependent binding interactions between a neighboring complex and F-actin, but the presence of the other αE-catenin domains weakens this effect. These results provide mechanistic insight to the cooperative binding of the cadherin-catenin complex to F-actin, which regulate dynamic cytoskeletal linkages in epithelial tissues.

Multi-level force-dependent allosteric enhancement of αE-catenin binding to F-actin by vinculin

“…Cooperative binding of αE-catenin to F-actin was also reported in solution [43] and in a biophysical study wherein a single b-catenin/aE-catenin heterodimer formed a short-lived slip bond, but a higher heterodimer surface density enabled the complex to form a directional catch bond with F-actin [35]. Studies from our laboratories likewise indicate that interactions between neighboring cadherin-catenin complexes facilitates F-actin binding under load [18,30]. These observations suggest that entry into a long-lived binding state may be facilitated by interactions between neighboring complexes.…”

“…We employed an optical trap (OT) assay [18, 29, 30] to compare the behavior of the ternary E-cadherin/β-catenin/αE-catenin complex with the quaternary complex formed by adding the vinculin head (Fig. 2A).…”

“…2C, D; Supplemental Information). The asymmetric catch bond mechanism was recently rationalized based on the structure of the αE-catenin actin- binding domain (ABD) bound to F-actin [36] and validated in single molecule experiments [30]. We modeled these effects by directionally-dependent distance parameters, x ij (-) and x ij (+) , denoting distance parameters for when force is oriented toward the F-actin (-) or (+) end, respectively (Supplemental Information, Table S1).…”