A conserved strand-swap mechanism drives heterodimerization of E-cadherin and P-cadherin

Cadherins are cell surface glycoproteins that mediate calcium-dependent cell-to-cell adhesion and maintain tissue integrity. Among classical cadherins, E-cadherin and P-cadherin are often co-expressed in epithelial tissues and contribute to adherens junction formation. E-cadherin is the principal component of adherens junctions in most epithelial cells, whereas P-cadherin is co-expressed with E-cadherin but is localized predominantly to the basal proliferative layer of epithelia. Although heterophilic interactions between these cadherins have been observed, the biophysical properties and molecular determinants governing their heterodimerization remain poorly defined. Here, we present a comprehensive biophysical characterization of the E-cadherin: P-cadherin heterodimer using surface plasmon resonance (SPR) and structure-guided mutational analyses. SPR studies revealed a direct, calcium-dependent interaction between their extracellular domains, with micromolar affinities that are physiologically relevant and comparable to those reported for classical cadherin interactions. Furthermore, structure-guided mutational analyses targeting residues within the membrane-distal ectodomain demonstrated that key residues identified in canonical strand-swap dimerization are also essential for the heterodimer formation.