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 language | English (US) |
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Article number | 5121 |
Journal | Nature communications |
Volume | 9 |
Issue number | 1 |
DOIs | |
State | Published - Dec 1 2018 |
Funding
Mammalian expression vector pCA-αEcat-GFP was a gift from M. Takeichi. R2/7 cells were kindly provided by F. van Roy. We thank the CMCF beamline at the Canadian Light Source for assisting data collection. We thank G. Seabrook for help with NMR. We are grateful to K. Kakiguchi and H. Endoh for their help with electron microscopy. We thank the CSB Imaging Facility (U. of Toronto) and the Center for Advanced Microscopy (Northwestern U.) for support. We thank D. Kirchenbuechler for help with PIV analysis. We thank T. Hakoshima and T.Q.P. Uyeda for technical advice. Funding: Foundation Theme grant from the Canadian Institutes for Health Research (CIHR) (to M.I.), the Princess Margaret Cancer Foundation (to M.I.), the Canadian Foundation for Innovation (to M.I., U.T. and R.F.-G.), a project grant from the CIHR (to U.T.), a grant from the Canada First Research Excellence Fund (to U.T. and R.F.-G.), National Institutes of Health (NIH) grants GM076561 (to C.J.G.), P01HL071643 (to C.J.G.), HL134800 (to C.J.G.) and GM129312 (to C.J.G., N.I., M.I., U.T. and D.E.L.), National Science Foundation (NSF) grant CHE 12-3755 (to D.E.L.), a grant supported by CREST from JST, Japan (to S.Y.), and NSF Graduate Research Program DGE-1324585 (to M.N.W.). M.I. is the Canadian Research Chair (CRC) in Cancer Structural Biology, U.T. is the CRC in Epithelial Polarity and Development, and R.F.-G. is the CRC in Quantitative Cell Biology and Morphogenesis.
ASJC Scopus subject areas
- General Chemistry
- General Biochemistry, Genetics and Molecular Biology
- General Physics and Astronomy
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Crystal structure of the alpha-N-catenin actin-binding domain H1 mutant
Ishiyama, N. (Contributor), Sarpal, R. (Contributor), Wood, M. N. (Contributor), Barrick, S. K. (Contributor), Nishikawa, T. (Contributor), Hayashi, H. (Contributor), Kobb, A. B. (Contributor), Flozak, A. S. (Contributor), Yemelyanov, A. (Contributor), Fernandez-Gonzalez, R. (Contributor), Yonemura, S. (Contributor), Leckband, D. E. (Contributor), Gottardi, C. J. (Contributor), Tepass, U. (Contributor) & Ikura, M. (Contributor), Protein Data Bank (PDB), Dec 19 2018
DOI: 10.2210/pdb6DUW/pdb, https://www.wwpdb.org/pdb?id=pdb_00006duw
Dataset
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Crystal structure of the alpha-N-catenin actin-binding domain H1 mutant
Ishiyama, N. (Contributor), Sarpal, R. (Contributor), Wood, M. N. (Contributor), Barrick, S. K. (Contributor), Nishikawa, T. (Contributor), Hayashi, H. (Contributor), Kobb, A. B. (Contributor), Flozak, A. S. (Contributor), Yemelyanov, A. (Contributor), Fernandez-Gonzalez, R. (Contributor), Yonemura, S. (Contributor), Leckband, D. E. (Contributor), Gottardi, C. J. (Contributor), Tepass, U. (Contributor) & Ikura, M. (Contributor), Protein Data Bank (PDB), Dec 19 2018
DOI: 10.2210/pdb6DUY/pdb, https://www.wwpdb.org/pdb?id=pdb_00006duy
Dataset
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Crystal structure of the alpha-E-catenin actin-binding domain
Ishiyama, N. (Contributor), Sarpal, R. (Contributor), Wood, M. N. (Contributor), Barrick, S. K. (Contributor), Nishikawa, T. (Contributor), Hayashi, H. (Contributor), Kobb, A. B. (Contributor), Flozak, A. S. (Contributor), Yemelyanov, A. (Contributor), Fernandez-Gonzalez, R. (Contributor), Yonemura, S. (Contributor), Leckband, D. E. (Contributor), Gottardi, C. J. (Contributor), Tepass, U. (Contributor) & Ikura, M. (Contributor), Protein Data Bank (PDB), Dec 19 2018
DOI: 10.2210/pdb6DV1/pdb, https://www.wwpdb.org/pdb?id=pdb_00006dv1
Dataset