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Nat Commun. 2018 Nov 30;9(1):5121. doi: 10.1038/s41467-018-07481-7.

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

Author information

1
Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada. noboru.ishiyama@uhnresearch.ca.
2
Department of Cell and Systems Biology, University of Toronto, Toronto, ON, M5S 3G5, Canada.
3
Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
4
Department of Chemistry, University of Illinois, Urbana, IL, 61801, USA.
5
Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada.
6
RIKEN Center for Life Science Technologies, Kobe, Hyogo, 650-0047, Japan.
7
Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, M5S 3G9, Canada.
8
Department of Cell Biology, Tokushima University Graduate School of Medical Science, Tokushima, 770-8503, Japan.
9
Department of Chemical and Biomolecular Engineering, University of Illinois, Urbana, IL, 61801, USA.
10
Department of Cellular and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
11
Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada. mitsu.ikura@uhnresearch.ca.
12
Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 1L7, Canada. mitsu.ikura@uhnresearch.ca.

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.

PMID:
30504777
PMCID:
PMC6269467
DOI:
10.1038/s41467-018-07481-7
[Indexed for MEDLINE]
Free PMC Article

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