Force-dependent allostery of the α-catenin actin-binding domain controls adherens junction dynamics and functions

alpha-catenin is a key mechanosensor that forms force-dependent interactions with F-actin, thereby coupling the cadherin-catenin complex to the actin cytoskeleton at adherens junctions (AJs). However, the molecular mechanisms by which alpha-catenin engages F-actin under tension remained elusive. Here we show that the alpha 1-helix of the alpha-catenin actin-binding domain (alpha cat-ABD) is a mechanosensing motif that regulates tension-dependent F-actin binding and bundling. alpha cat-ABD containing an alpha 1-helix-unfolding mutation (H1) shows enhanced binding to F-actin in vitro. Although full-length alpha-catenin-H1 can generate epithelial monolayers that resist mechanical disruption, it fails to support normal AJ regulation in vivo. Structural and simulation analyses suggest that alpha 1-helix allosterically controls the actin-binding residue V796 dynamics. Crystal structures of alpha cat-ABD-H1 homodimer suggest that alpha-catenin can facilitate actin bundling while it remains bound to E-cadherin. We propose that force-dependent allosteric regulation of alpha cat-ABD promotes dynamic interactions with F-actin involved in actin bundling, cadherin clustering, and AJ remodeling during tissue morphogenesis.