Identification and Characterization of Novel Macromolecular Assemblies Responsible for Cell Adhesion

Cadherins and nectins are cell surface glycoproteins that function as cell adhesion molecules (CAMs) to drive the adhesion of cells and thereby organize them into higher‐ordered structures during early development. Homophilic associations among the cadherins and homophilic as well as heterophilic associations among the nectins lead to the formation of adherens junction that drives cell‐to‐cell adhesion. However, several studies suggest for the existence of complex cross‐talk among these CAMs, which remains to be explored in greater detail. Based on SPR‐based protein‐protein interaction studies followed by structure‐guided mutagenesis and complementary biophysical analyses, we observed specific heterophilic associations among cadherins and nectin family members mediated through their membrane distal ectodomains. In particular, N‐cadherin was found to interact with nectin‐2, E‐cadherin to interact with nectin‐4, and E‐cadherin and N‐cadherin were also found to interact with each other. In conclusion to these observations, the biophysical and biochemical studies imply for direct heterophilic recognition and crosstalk among nectins and cadherins and the results obtained elaborate how these novel macromolecular assemblies can also be a part of adherens junction to drive physiologically relevant cell‐cell adhesion.