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

*Corresponding author for this work

Research output: Contribution to journalArticle

11 Scopus citations

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

    Fingerprint

ASJC Scopus subject areas

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

Cite this

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