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 Gottardi, Ulrich Tepass, Mitsuhiko Ikura

*Corresponding author for this work

Research output: Contribution to journalArticle

2 Citations (Scopus)

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

Adherens Junctions
Catenins
Actins
helices
Cadherins
mutations
Allosteric Regulation
interactions
crystal structure
Actin Cytoskeleton
Morphogenesis
Cluster Analysis

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., ... 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
Ishiyama, Noboru ; Sarpal, Ritu ; Wood, Megan N. ; Barrick, Samantha K. ; Nishikawa, Tadateru ; Hayashi, Hanako ; Kobb, Anna B. ; Flozak, Annette S. ; Yemelyanov, Alex ; Fernandez-Gonzalez, Rodrigo ; Yonemura, Shigenobu ; Leckband, Deborah E. ; Gottardi, Cara ; Tepass, Ulrich ; Ikura, Mitsuhiko. / Force-dependent allostery of the α-catenin actin-binding domain controls adherens junction dynamics and functions. In: Nature communications. 2018 ; Vol. 9, No. 1.
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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.",
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Ishiyama, N, Sarpal, R, Wood, MN, Barrick, SK, Nishikawa, T, Hayashi, H, Kobb, AB, Flozak, AS, Yemelyanov, A, Fernandez-Gonzalez, R, Yonemura, S, Leckband, DE, Gottardi, C, Tepass, U & Ikura, M 2018, 'Force-dependent allostery of the α-catenin actin-binding domain controls adherens junction dynamics and functions', Nature communications, vol. 9, no. 1, 5121. https://doi.org/10.1038/s41467-018-07481-7

Force-dependent allostery of the α-catenin actin-binding domain controls adherens junction dynamics and functions. / Ishiyama, Noboru; Sarpal, Ritu; Wood, Megan N.; Barrick, Samantha K.; Nishikawa, Tadateru; Hayashi, Hanako; Kobb, Anna B.; Flozak, Annette S.; Yemelyanov, Alex; Fernandez-Gonzalez, Rodrigo; Yonemura, Shigenobu; Leckband, Deborah E.; Gottardi, Cara; Tepass, Ulrich; Ikura, Mitsuhiko.

In: Nature communications, Vol. 9, No. 1, 5121, 01.12.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Force-dependent allostery of the α-catenin actin-binding domain controls adherens junction dynamics and functions

AU - Ishiyama, Noboru

AU - Sarpal, Ritu

AU - Wood, Megan N.

AU - Barrick, Samantha K.

AU - Nishikawa, Tadateru

AU - Hayashi, Hanako

AU - Kobb, Anna B.

AU - Flozak, Annette S.

AU - Yemelyanov, Alex

AU - Fernandez-Gonzalez, Rodrigo

AU - Yonemura, Shigenobu

AU - Leckband, Deborah E.

AU - Gottardi, Cara

AU - Tepass, Ulrich

AU - Ikura, Mitsuhiko

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

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