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

Noboru Ishiyama, Ritu Sarpal, Megan N. Wood, Samantha K. Barrick, Tadateru Nishikawa, Hanako Hayashi, Anna B. Kobb, Annette S. Flozak, Alex Yemelyanov, Rodrigo Fernandez-Gonzalez, Shigenobu Yonemura, Deborah E. Leckband, Cara J. Gottardi, Ulrich Tepass, Mitsuhiko Ikura

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number5121
JournalNature communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Ishiyama, N., Sarpal, R., Wood, M. N., Barrick, S. K., Nishikawa, T., Hayashi, H., Kobb, A. B., Flozak, A. S., Yemelyanov, A., Fernandez-Gonzalez, R., Yonemura, S., Leckband, D. E., Gottardi, C. J., Tepass, U., & Ikura, M. (2018). Force-dependent allostery of the α-catenin actin-binding domain controls adherens junction dynamics and functions. Nature communications, 9(1), [5121]. https://doi.org/10.1038/s41467-018-07481-7