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Abstract
α-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 α-catenin engages F-actin under tension remained elusive. Here we show that the α1-helix of the α-catenin actin-binding domain (αcat-ABD) is a mechanosensing motif that regulates tension-dependent F-actin binding and bundling. αcat-ABD containing an α1-helix-unfolding mutation (H1) shows enhanced binding to F-actin in vitro. Although full-length α-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 α1-helix allosterically controls the actin-binding residue V796 dynamics. Crystal structures of αcat-ABD-H1 homodimer suggest that α-catenin can facilitate actin bundling while it remains bound to E-cadherin. We propose that force-dependent allosteric regulation of αcat-ABD promotes dynamic interactions with F-actin involved in actin bundling, cadherin clustering, and AJ remodeling during tissue morphogenesis.
Highlights
The mechanical coupling of intercellular adhesion proteins to the cytoskeleton plays a key role in balancing the integrity and plasticity of epithelial tissues
We found that the deletion of residues 663-696 from the actinbinding domain (ABD) was associated with an unusual accumulation of cadherincatenin-filamentous actin (F-actin) complexes in the cytoplasm after trypsinization of cell monolayers (Supplementary Fig. 1b, c), and delayed reformation of adherens junctions (AJs) with a unique square wave-like arrangement (Supplementary Fig. 2a)
We show that the unique molecular features of αcat-ABD, α1helix, V796, and βH, confer mechanosensitivity to α-catenin and its ability to dynamically regulate and reorganize actin filaments directly associated with cadherin-catenin complexes at intercellular junctions
Summary
The mechanical coupling of intercellular adhesion proteins to the cytoskeleton plays a key role in balancing the integrity and plasticity of epithelial tissues. The enormous versatility of cadherin-mediated cell adhesion in tissue morphogenesis and homeostasis requires catenin-dependent regulation of the dynamic cadherin-actin interface in response to variable tension. Α-catenin is an actin-binding and actin-bundling protein responsible for connecting the cadherin-catenin complex to filamentous actin (F-actin) at AJs5–8 It plays critical roles in development and tissue homeostasis across the metazoans[9,10,11,12], and α-catenin gene mutations have been linked to a variety of physiological abnormalities[13,14,15], including tumor metastasis[16]. Loss and gain of Factin binding propensity dramatically compromises α-catenin function in morphogenesis Based on these results, we propose a new mechanism of the force-dependent, dynamic cadherin-actin linkage regulated by the ABD of α-catenin
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