TY - JOUR
T1 - Force-induced changes of α-catenin conformation stabilize vascular junctions independently of vinculin
AU - Duong, Cao Nguyen
AU - Brückner, Randy
AU - Schmitt, Martina
AU - Nottebaum, Astrid F.
AU - Braun, Laura J.
AU - Meyer zu Brickwedde, Marika
AU - Ipe, Ute
AU - Vom Bruch, Hermann
AU - Schöler, Hans R.
AU - Trapani, Giuseppe
AU - Trappmann, Britta
AU - Ebrahimkutty, Mirsana P.
AU - Huveneers, Stephan
AU - de Rooij, Johan
AU - Ishiyama, Noboru
AU - Ikura, Mitsuhiko
AU - Vestweber, Dietmar
PY - 2021/12/15
Y1 - 2021/12/15
N2 - Cadherin-mediated cell adhesion requires anchoring via the β-catenin-α-catenin complex to the actin cytoskeleton, yet, α-catenin only binds F-actin weakly. A covalent fusion of VE-cadherin to α-catenin enhances actin anchorage in endothelial cells and strongly stabilizes endothelial junctions in vivo, blocking inflammatory responses. Here, we have analyzed the underlying mechanism. We found that VE-cadherin-α-catenin constitutively recruits the actin adaptor vinculin. However, removal of the vinculin-binding region of α-catenin did not impair the ability of VE-cadherin-α-catenin to enhance junction integrity. Searching for an alternative explanation for the junction-stabilizing mechanism, we found that an antibody-defined epitope, normally buried in a short α1-helix of the actin-binding domain (ABD) of α-catenin, is openly displayed in junctional VE-cadherin-α-catenin chimera. We found that this epitope became exposed in normal α-catenin upon triggering thrombin-induced tension across the VE-cadherin complex. These results suggest that the VE-cadherin-α-catenin chimera stabilizes endothelial junctions due to conformational changes in the ABD of α-catenin that support constitutive strong binding to actin.
AB - Cadherin-mediated cell adhesion requires anchoring via the β-catenin-α-catenin complex to the actin cytoskeleton, yet, α-catenin only binds F-actin weakly. A covalent fusion of VE-cadherin to α-catenin enhances actin anchorage in endothelial cells and strongly stabilizes endothelial junctions in vivo, blocking inflammatory responses. Here, we have analyzed the underlying mechanism. We found that VE-cadherin-α-catenin constitutively recruits the actin adaptor vinculin. However, removal of the vinculin-binding region of α-catenin did not impair the ability of VE-cadherin-α-catenin to enhance junction integrity. Searching for an alternative explanation for the junction-stabilizing mechanism, we found that an antibody-defined epitope, normally buried in a short α1-helix of the actin-binding domain (ABD) of α-catenin, is openly displayed in junctional VE-cadherin-α-catenin chimera. We found that this epitope became exposed in normal α-catenin upon triggering thrombin-induced tension across the VE-cadherin complex. These results suggest that the VE-cadherin-α-catenin chimera stabilizes endothelial junctions due to conformational changes in the ABD of α-catenin that support constitutive strong binding to actin.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85122903987&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/34851405
U2 - https://doi.org/10.1242/jcs.259012
DO - https://doi.org/10.1242/jcs.259012
M3 - Article
C2 - 34851405
SN - 0021-9533
VL - 134
JO - Journal of Cell Science
JF - Journal of Cell Science
IS - 24
ER -