Divergence of structural strategies for E-cadherin homophilic binding among bilaterians

Abstract

Homophilic binding of E-cadherins through their ectodomains is fundamental to epithelial cell-cell adhesion. Despite this, E-cadherin ectodomains have evolved differently in the vertebrate and hexapod lineages. Of the five rod-like, tandemly aligned extracellular cadherin domains (ECs) of vertebrate E-cadherin, the tip EC plays a pivotal role in binding interactions. Comparatively, the N-terminal six consecutive ECs of Drosophila E-cadherin, DE-cadherin, can mediate adhesion; however, the underlying mechanism is unknown. Here we report atomic force microscopy imaging of DE-cadherin ECs. We identified a tightly folded globular structure formed by the four N-terminal-most ECs stabilized by the subsequent two ECs. Analysis of hybrid cadherins of different hexapods indicated association of the E-cadherin globular portion with the determinants of homophilic binding specificity. The second to fourth ECs were identified as the minimal portion capable of mediating exclusive homophilic binding specificity. Our findings suggested that the N-terminal-most four ECs of hexapod E-cadherin are functionally comparable with the N-terminal-most single EC of vertebrate E-cadherin, but that their mechanisms might significantly differ. This work illuminates the divergence of structural strategies for E-cadherin homophilic binding among bilaterians.