Molecular and structural bases of interaction between extracellular domains of nectin‐2 and N‐cadherin

: Cell adhesion molecules such as nectins and cadherins play important role in the formation of adherens junction. While nectins interact through their extracellular domains in both homophilic and heterophilic manner among themselves, extracellular domains of cadherins participate only in homophilic fashion to mediate cell-cell adhesion. It is well established that nectins recruit cadherins in the adhesion sites through an interplay of adaptor molecules in the cytoplasmic side thereby increasing the effective concentration of both the adhesion molecules on the cell surface. This study provides molecular and structural bases of the novel interaction between extracellular domains of nectin-2 and N-cadherin, by which nectins can also recruit cadherins at the site of adherens junction through an adaptor-independent mechanism. Surface plasmon resonance study demonstrates that nectin-2 can directly recognize N-cadherin with a KD of 3.5 ± 0.6 μM which is physiologically relevant considering the affinities between other cell adhesion molecules including cadherin dimerization. Furthermore, structural analysis of currently available homodimeric structures of both nectin-2 and N-cadherin followed by molecular docking as well as complementary mutagenesis studies revealed the binding interface of this novel interaction.