Structure of artificial and natural VE-cadherinbased adherens junctions

Abstract

In vascular endothelium, adherens junctions between endothelial cells are composed of VE-cadherin (vascular endothelial cadherin), an adhesive receptor that is crucial for the proper assembly of vascular structures and the maintenance of vascular integrity. As a classical cadherin, VE-cadherin links endothelial cells together by homophilic interactions mediated by its extracellular part and associates intracellularly with the actin cytoskeleton via catenins. Although, from structural crystallographic data, a dimeric structure arranged in a trans orientation has emerged as a potential mechanism of cell-cell adhesion, the cadherin organization within adherens junctions remains controversial. Concerning VE-cadherin, its extracellular part possesses the capacity to self-associate in solution as hexamers consisting of three antiparallel cadherin dimers. VE-cadherin-based adherens junctions were reconstituted in vitro by assembly of a VE-cadherin EC (extracellular repeat) 1-EC4 hexamer at the surfaces of liposomes. The artificial adherens junctions revealed by cryoelectron microscopy appear as a two-dimensional self-assembly of hexameric structures. This cadherin organization is reminiscent of that found in native desmosomal junctions. Further structural studies performed on native VE-cadherin junctions would provide a better understanding of the cadherin organization within adherens junctions. Homophilic interactions between cadherins are strengthened intracellularly by connection to the actin cytoskeleton. Recently, we have discovered that annexin 2, an actin-binding protein connects the VE-cadherin-catenin complex to the actin cytoskeleton. This novel link is labile and promotes the endothelial cell switch from a quiescent to an angiogenic state.

Neural Wiskott-Aldrich Syndrome Protein (N-WASP)-mediated p120-Catenin Interaction with Arp2-Actin Complex Stabilizes Endothelial Adherens Junctions

“…Homotypic adhesion between VE-cadherin from adjacent endothelial cells constitutes AJs, which form the primary barrier in endothelial cells (4). Stable AJs require interaction of VE-cadherin with catenins as well as the cortical actin ring (5-10).…”

Cadherin-dependent mechanotransduction depends on ligand identity but not affinity

“…Possible candidates are protocadherins (Chen and Gumbiner, 2006;Deplazes et al, 2009;Taveau et al, 2008), receptor tyrosine kinases (Brady-Kalnay et al, 1995;Hellberg et al, 2002;McLachlan and Yap, 2011) or growth factor receptors (Perrais et al, 2007;Shibamoto et al, 1994;Tzima et al, 2005;Williams et al, 2001). Recent findings demonstrated a role for protocadherin-19 in the regulation of N-cadherindependent cell-cell adhesion and migration (Papusheva and Heisenberg, 2010;Taveau et al, 2008), and PAPC regulates the adhesive activity of C-cadherin during Xenopus morphogenesis (Chen and Gumbiner, 2006). Nevertheless, the mechanoselectivity demonstrated here with five cell lines and three classical cadherin subtypes demonstrates that cadherin selectivity can modulate both intersurface adhesion energies and cell mechanics, both of which instruct morphogenesis and maintain compartment barriers in mature tissues.…”

Structure and Biochemistry of Cadherins and Catenins

“…These structures, which have been studied by classical EM and tomography methods (He et al 2003;AlAmoudi et al 2007), are densely packed with cadherins, raising the question of whether specific lateral interactions of cadherins on the same cell contribute to the higher-order structure of the junctions. Furthermore, EM studies of liposomes coated with the ectodomain of the type II VE-cadherin reveal junction-like structures (Taveau et al 2008), suggesting that the ectodomain alone may be sufficient to specify junction structure. These observations have prompted the search for "cis" or lateral interfaces between cadherin ectodomains, but so far, few solid answers have arisen.…”