Calcium-modulated cis and trans E-cadherin EC1-2 interactions play a key role in formation, dynamics and plasticity of cadherin junctions

Classical cadherins are ubiquitous calcium-dependent adhesive glycoproteins required in junction formation in metazoans. Calcium ions are essential for cadherin biological activity, but how they act in synergy is still a matter of controversy. We investigated by cryo-electron microscopy and cryo-electron tomography, a biomimetic system consisting of liposomes decorated with the two first E-cadherin extracellular modules, previously reported as functionally essential in junction formation. We showed that E-cadherin extracellular modules 1 and 2 are sufficient to form junctions in presence of calcium. Together with the first adhesive contacts, we observed the formation of cadherin patches and quasi-crystalline structures on the free surface of proteoliposomes suggesting that calcium complexation induces the self-interaction of the E-cadherin extracellular modules 1 and 2 through cis interactions. We propose that these calcium-dependent cadherin nanoplatforms, by facilitating the formation frequency of trans interactions, most probably favor the formation of junctions. We also observed a cooperative effect between trans and cis interactions leading to the protein depletion of liposome surfaces. Additionally, Cryo-electron tomography experiments performed on extracellular E-cadherin modules 1 and 2-mediated junctions revealed the coexistence of different molecular arrangements previously described from crystallography studies. Thus, this study provides a new insight into biophysical mechanisms underlying how calcium binding modulates cadherin adhesive function, in showing that E-cadherin 1 and 2 modules play a key role through their intrinsic ability to form multiple calcium-dependent cis and trans interactions, in the formation of cadherin junctions contributing to the dynamics and plasticity of cadherin-mediated cell junctions.