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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, the 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.

Glycogen synthase kinase-3 (GSK-3) is a key regulator of many cellular signaling pathways. Unlike most kinases, GSK-3 is controlled by inhibition rather than by specific activation. In the insulin and several other signaling pathways, phosphorylation of a serine present in a conserved sequence near the amino terminus of GSK-3 generates an auto-inhibitory peptide. In contrast, Wnt/β-catenin signal transduction requires phosphorylation of Ser/Pro rich sequences present in the Wnt co-receptors LRP5/6, and these motifs inhibit GSK-3 activity. We present crystal structures of GSK-3 bound to its phosphorylated N-terminus and to two of the phosphorylated LRP6 motifs. A conserved loop unique to GSK-3 undergoes a dramatic conformational change that clamps the bound pseudo-substrate peptides, and reveals the mechanism of primed substrate recognition. The structures rationalize target sequence preferences and suggest avenues for the design of inhibitors selective for a subset of pathways regulated by GSK-3. DOI: http://dx.doi.org/10.7554/eLife.01998.001, eLife digest Cells need to be able to respond to changes in the body, such as changes in hormone levels or the arrival of a pathogen such as a virus. Proteins acting in signaling pathways—where one protein switches ‘on’ or ‘off’ the next protein in the pathway—allow the detection of different changes or signals to be translated in the appropriate response. The properties of a protein often depend on its shape, and many proteins change shape when they are switched ‘on’ and ‘off’. Moreover, the ability to change shape allows a protein to interact with many other proteins and to be involved in many different signaling pathways. The enzyme GSK-3 is a protein that is involved in several pathways, and it controls other proteins by adding chemical tags, called phosphate groups, to them. Unlike many other enzymes, GSK-3’s default state is to be permanently switched on, and it can be switched off in a number of different ways. When a cell detects the hormone insulin, for example, another enzymes adds a phosphate group to a site near one end of GSK-3 to switch it off. Alternatively, when a cell recognises a different signaling molecule, called Wnt, a phosphate group is added to yet another protein, which then binds to and switches off GSK-3. To explore the workings of GSK-3 in greater detail, Stamos et al. solved the three-dimensional structure of the enzyme that had been switched off in these two ways. In the insulin pathway, the region near to one end of GSK-3 that contains the added phosphate group was shown to bind to and block the site on the enzyme that usually binds to its target (i.e., to the next protein in the signaling pathway). In the Wnt pathway, remarkably, the same site on GSK-3 was blocked in a very similar way by the piece of the other protein with the phosphate group added. GSK-3 is a potential drug target for the treatment of several diseases, such as diabetes and neurological disorders. However, as this enzyme is involved in multiple pathways, it has been hard to find drugs to treat any one condition without side effects. Uncovering subtle differences in how GSK-3 can be controlled in different pathways could, in the future, help with efforts to develop more specific drugs to target GSK-3 to treat these diseases. DOI: http://dx.doi.org/10.7554/eLife.01998.002