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 J.
AU - Tepass, Ulrich
AU - Ikura, Mitsuhiko
N1 - Mammalian expression vector pCA-\u03B1Ecat-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.
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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85057789357
UR - https://www.scopus.com/pages/publications/85057789357#tab=citedBy
U2 - 10.1038/s41467-018-07481-7
DO - 10.1038/s41467-018-07481-7
M3 - Article
C2 - 30504777
AN - SCOPUS:85057789357
SN - 2041-1723
VL - 9
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5121
ER -