Transient interactions drive the lateral clustering of Cadherin-23 on membrane

Cis and trans-interactions among cadherins secure multicellularity. While the molecular structure of trans-interactions of cadherins is well understood, identifying the molecular cues that spread the cis-interactions two-dimensionally is still ongoing. Here, we report that transient, weak, multivalent, and spatially distributed hydrophobic interactions, requisite for liquid-liquid phase separations of biomolecules in solution, alone can drive the lateral-clustering of cadherin-23 on a membrane. No specific cis-dimer interactions are required for the lateral clustering. In cellulo, the cis-clustering accelerates the cell-cell adhesion and, thus, contributes in cell-adhesion kinetics along with strengthening the junction. Although the physiological connection of cis-clustering with rapid adhesion is yet to be explored, M2-macrophages that predominantly express cadherin-23 undergo fast attachments to circulatory tumor cells during metastasis.