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

ABSTRACT: ?-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 ?-catenin engages F-actin under tension remained elusive. Here we show that the ?1-helix of the ?-catenin actin-binding domain (?cat-ABD) is a mechanosensing motif that regulates tension-dependent F-actin binding and bundling. ?cat-ABD containing an ?1-helix-unfolding mutation (H1) shows enhanced binding to F-actin in vitro. Although full-length ?-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 ?1-helix allosterically controls the actin-binding residue V796 dynamics. Crystal structures of ?cat-ABD-H1 homodimer suggest that ?-catenin can facilitate actin bundling while it remains bound to E-cadherin. We propose that force-dependent allosteric regulation of ?cat-ABD promotes dynamic interactions with F-actin involved in actin bundling, cadherin clustering, and AJ remodeling during tissue morphogenesis.

SUBMITTER: Ishiyama N

PROVIDER: S-EPMC6269467 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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

Ishiyama Noboru N Sarpal Ritu R Wood Megan N MN Barrick Samantha K SK Nishikawa Tadateru T Hayashi Hanako H Kobb Anna B AB Flozak Annette S AS Yemelyanov Alex A Fernandez-Gonzalez Rodrigo R Yonemura Shigenobu S Leckband Deborah E DE Gottardi Cara J CJ Tepass Ulrich U Ikura Mitsuhiko M

Nature communications 20181130 1

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 ...[more]

PMID: 30504777

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Project description:Background: Negative-pressure wound therapy has become widely available in modern chronic wound cares. Accelerated keratinocyte (HaCaT cell) movements and decreased E-cadherin expressions induced by the applied negative pressure gradient of 125 mmHg (NP) have been reported in previous studies. However, the molecular mechanism for E-cadherin regulations under NP remains unexplored. We highlighted the signal transduction involved in NP-induced E-cadherin regulation for keratinocytes in the study. Results: Microarray results showed that catenin 1 (CTNND1) gene, the gene encoding the p120-catenin (p120ctn) in cell-cell junctions, was significantly (p = 0.0005) upregulated in HaCaT cells under NP for 12 hours in comparison with those at ambient pressure (AP). Cell fractionations and immunoblotting data showed that NP increased p120ctn phosphorylation, and resulted in p120ctn translocation from the plasma membrane to the cytoplasm. Fluorescent stains suggested that NP diminished the co-localization of p120ctn and E-cadherin on the plasma membrane. Similar phenomenon was also observed in the cells with overexpressed p120ctn at NP. Interestingly, overexpression of dN- p120ctn, a deletion mutant of p120ctn without the N-terminal phosphorylation sites, restored the adherens junctions (AJ) at NP. Knockdown of p120ctn with lentiviral small hairpin RNA not only diminished E-cadherin expressions but also accelerated cell movement at AP. Conclusions: Phosphorylation of p120ctn is endowed to respond rapidly to NP and contributes to the AJ disassembly. This NP-induced E-cadherin downregulation can possibly accelerate wound-healing process. Conclusions: Phosphorylation of p120ctn is endowed to respond rapidly to NP and contributes to the AJ disassembly. This NP-induced E-cadherin downregulation can possibly accelerate wound-healing process. HaCaT cells under negative pressure (NP) gradient of 125 mmHg for 12 hours in comparison with those at ambient pressure (AP) were tested for RNA extraction and hybridization on Affymetrix microarrays. The experiments have been biological replicated three times. The differential expression gene between NP and AP were selected and validated with qPCR method.

Dataset Information

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

Publications

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

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