Regulation of α-catenin conformation at cadherin adhesions

Abstract

Cells in our body utilize a variety of adaptor proteins for transmitting context specific signals that arise from the cellular microenvironment. Adaptor proteins lack enzymatic activity and typically perform their function by acting as scaffolds that bind other signaling proteins. While most adaptor proteins are functionally modulated by biochemical alterations such as phosphorylation, a subset of adaptor proteins are functionally modulated by a mechanical alteration in their structure that makes cryptic sites available for binding to downstream signaling proteins. α-catenin is one such adaptor protein that localizes to cadherin-based cell adhesions by binding the membrane-localized cadherin-β-catenin complex at one side and the cytosolic F-actin on the other side. An increase in actomyosin tension is directly relayed to α-catenin resulting in a change in its conformation making cryptic binding sites accessible to its interacting partners. Here, I describe an updated view of the mechanical regulation of α-catenin in the context of cellular adhesion, including the role of cadherin clustering in its activation.

Decreased Interfacial Dynamics Caused by the N501Y Mutation in the SARS-CoV-2 S1 Spike:ACE2 Complex

“…2A). [27–33] However, RMSD analysis of the backbone Cα atoms of the proteins, ACE2 and S1-RBD individually taken over the entire course of simulations time did not show any clearly discernable trend for structural evolution of amino acid residues in the complex (Figure 2B,C). This suggests that any alteration in the biochemical interaction between the two proteins likely arises due to changes in the dynamics of specific, individual residues in the proteins.…”

“…The latter is suggestive of the possibility of an allosteric effect of the increased interaction of Y501 in the mutant ACE2-S1-RBD complex as compared to N501 in the wild type complex. [27][28][29][30][31][32][33] Following these analyses, we determined the residue-residue distances (based on the center of mass of the residues) of key residues at the ACE2-S1-RBD interface as they evolved during the span of the simulations (Figure 3A). First, N501 residue in the wild type complex showed a substantially higher structural fluctuation in comparison to Y501 in the mutant complex.…”

“…The latter is suggestive of the possibility of an allosteric effect of the increased interaction of Y501 in the mutant ACE2-S1-RBD complex as compared to N501 in the wild type complex. [27–33]…”

Role of Actin Cytoskeleton in E-cadherin-Based Cell–Cell Adhesion Assembly and Maintenance

“…phosphorylation of specific residues 115 or binding of α-catenin interacting proteins such as α-actinin 116 . These posit that perhaps α-catenin explores the 'open' conformation in the absence of interaction of F-actin and, thus, application of force, 81,[117][118][119][120] and, thus, binding of F-actin to these α-catenin initiates E-cadherin clustering through application of mechanical force, especially on viscous bilayers, 88 which perhaps results in the activation of more α-catenin molecules as seen in the staining experiments. Additionally, binding of vinculin, which is seen to specifically associate with E-cadherin clusters at the cell periphery, 80 to the conformationally activated α-catenin molecules could further strengthen the interaction of the E-cadherin-β-catenin-α-catenin complex with the F-actin and thus efficient clustering leading to the formation of mature E-cadherin adhesion.…”

“…Recent studies have pointed to the mechanosensory role of α-catenin in that it undergoes a force-dependent conformational change from a 'closed' to an 'open' structure. [79][80][81] This results in the accessibility of a cryptic binding site for vinculin, another mechanosensitive adaptor protein homologous to α-catenin, that can also bind F-actin. 82,83 Thus, an increase in the mechanical tension in the epithelial tissue results in an increased F-actin binding and strengthening of the cadherin adhesion, thus enabling cells to withstand such an increased tension.…”