The molecular architecture of cadherins in native epidermal desmosomes

Desmosomes are cadherin- based adhesive intercellular junctions, which are present in tissues such as heart and skin. Despite considerable efforts, the molecular interfaces that mediate adhesion remain obscure. Here we apply cryo- electron tomography of vitreous sections from human epidermis to visualize the three- dimensional molecular architecture of desmosomal cadherins at close- to- native conditions. The three- dimensional reconstructions show a regular array of densities at similar to 70 angstrom intervals along the midline, with a curved shape resembling the X- ray structure of C- cadherin, a representative 'classical' cadherin. Model- independent three- dimensional image processing of extracted sub- tomograms reveals the cadherin organization. After fitting the C- cadherin atomic structure into the averaged sub- tomograms, we see a periodic arrangement of a trans W- like and a cis V- like interaction corresponding to molecules from opposing membranes and the same cell membrane, respectively. The resulting model of cadherin organization explains existing two- dimensional data and yields insights into a possible mechanism of cadherin- based cell adhesion.