Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada.
Department of Cell and Systems Biology, University of Toronto, Toronto, ON, M5S 3G5, Canada.
Nat Commun. 2018 Nov 30;9(1):5121. doi: 10.1038/s41467-018-07481-7.
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.
α-连环蛋白是一种关键的机械感受器，它与 F-肌动蛋白形成力依赖性相互作用，从而将钙粘蛋白-连环蛋白复合物与粘着连接（AJs）处的肌动蛋白细胞骨架连接起来。然而，α-连环蛋白在张力下与 F-肌动蛋白结合的分子机制仍然难以捉摸。在这里，我们表明α-连环蛋白肌动蛋白结合域（αcat-ABD）的α1-螺旋是一种机械感应基序，可调节张力依赖性 F-肌动蛋白结合和束集。含有α1-螺旋展开突变（H1）的αcat-ABD 在体外表现出增强的与 F-肌动蛋白的结合。尽管全长α-连环蛋白-H1 可以产生抵抗机械破坏的上皮单层，但它不能在体内支持正常的 AJ 调节。结构和模拟分析表明，α1-螺旋变构控制着肌动蛋白结合残基 V796 的动力学。αcat-ABD-H1 同源二聚体的晶体结构表明，α-连环蛋白可以促进肌动蛋白的束集，同时仍然与 E-钙粘蛋白结合。我们提出，αcat-ABD 的力依赖性变构调节促进了与 F-肌动蛋白的动态相互作用，这些相互作用参与了组织形态发生过程中的肌动蛋白束集、钙粘蛋白聚集和 AJ 重塑。
