Cis-clustering of cadherin-23 controls the kinetics of cell-cell adhesion

Abstract Cis and trans-interactions in cadherins are the foundations of cellular adhesions in multicellular organisms. While the trans-interactions mediate the intercellular attachment, the cis-interaction is presumed as reinforcement to trans. Thus, trans precedes cis has been the well-accepted model in cadherin adhesion. The stronger affinity of trans-binding over cis has been the decisive influence in the trans first model. Here we show that cadherin-23, a non-classical cadherin with an extended extracellular region, can undergo cis-clustering in solution independent of trans and phase separate as liquid droplets. Using single-molecule measurements, we decipher that weaker cis-interactions favor the cis-clustering. In-cellulo, the cis-clustering is manifested as puncta, a common feature in non-classical cadherin junctions, and accelerates the cell adhesion. The cis-clustering thus kinetically controls cell-adhesion before trans-binding. Notably, M2-macrophages predominantly express cadherin-23 and rapidly attach to circulatory tumor cells during metastatic migration. However, the relation of cis-clustering with rapid cell-cell adhesion in physiology is not yet established