The core p120-binding region of classical cadherins is well conserved. (A) Schematic illustration of the cadherin–catenin complex. Extracellular cadherin domains mediate adhesion through trans-interactions with cadherins on the adjacent cell. The cadherin juxtamembrane domain binds to p120, and the catenin-binding domain interacts with β-catenin (β-cat). β-Catenin and α-catenin link the cadherin with the actin cytoskeleton (gray) through a mechanism that is not fully understood. CBD, catenin-binding domain; JMD, juxtamembrane domain. (B) Predicted molecular interface between VE-cadherin and p120-catenin. A simulated 3D model of VE-cadherin juxtamembrane domain residues 646–664 bound to the armadillo repeat domain of p120 (surface electrostatic potential: blue, positive; red, negative) was constructed based on the crystal structure of the E-cadherin juxtamembrane domain bound to p120 (Protein Data Bank accession no. 3L6X). Selected residues of VE-cadherin and p120 are labeled in magenta and black, respectively. (C) Multiple sequence alignment of classical cadherins from human (hm), mouse (ms), and Drosophila (dr). Conserved residues are highlighted in green. The core p120-binding region (residues 644–664), which mediates the strongest interactions between the cadherin and p120, is indicated. Other notable features are marked below the alignment: 1, E-cadherin dileucine endocytic signal; 2, E-cadherin Y753 and Y754 Src phosphorylation sites required for Hakai-mediated ubiquitination of E-cadherin; 3–5, VE-cadherin mutations used in Figs. 3, 4, 5, 6, 7, 8, 9, and 10; Δ644 and Δ657, location of VE-cadherin truncation mutations used in Fig. 2.