Trans- and cis-interaction dynamics of cadherin complexes on membranes visualized by high-speed atomic force microscopy.

Classical cadherin-mediated cell-cell adhesion is important for maintaining the animal body and defects in adhesion cause severe diseases. The combination of trans- (between cells) and cis- (on the same membrane) interactions of the extracellular domains of cadherins is necessary for cadherin clustering in cell-cell junctions, which is essential for robust tissue formation. However, the solution structure and interaction dynamics of trans/cis-binding cadherin complexes have not been observed because of technical limitations; therefore, the cadherin clustering mechanism is not well understood. In this study, we reconstituted trans/cis-binding cadherin complexes on membranes and visualized their structure and dynamics using high-speed atomic force microscopy. Our method revealed trans-strand-swap interactions through flipping and hopping motions and cis-interactions, which contributed to multiple interaction patterns on the membrane. In addition, we observed cadherin complex structures that were distinct from those in crystal structures. These results suggest that cadherins adopt dynamic and diverse conformations through multiple assembly pathways on the membrane.