Correlations in cadherin-mediated membrane adhesion dynamics: Molecular concentration switch and diffusion dial

Cell adhesion, fundamental to many physiopathological processes, is a tightly regulated multiscale phenomenon. In spite of immense advances in phenomenological description of the steps involved in adhesion, a full understanding of the coupling of bond kinetics and global dynamics of adhesion is still lacking even for model lipid membranes, especially when the adhesion is mediated by sparse and weak bonds. We report combined experimental and theoretical results showing that membrane adhesion dynamics depend strongly on binder concentration and only weakly on binder diffusion. A minimal adhesion system consisting of cadherin-decorated giant unilamellar vesicles (GUVs) and supported lipid bilayers (SLBs) is imaged using reflection interference contrast microscopy to follow the growth dynamics of the adhesion zone between the GUV and the SLB membranes. Cadherins diffuse on the GUV membrane, while on the SLB, they are either laterally mobile within the bilayer or immobilized; the concentration of cadherins on both membranes is systematically varied. Quantitative analysis shows that both the equilibrium state and adhesion dynamics depend strongly on ligand concentration, with higher concentrations leading to faster and stronger adhesion. At fixed concentration, cadherin mobility further enhances and accelerates adhesion. To explain this result, we construct a multiscale Monte Carlo simulation of the GUV spreading dynamics, due to cadherin trans binding using an adaptive Euler method. Simulations reveal that membrane-mediated trans interactions between cadherins lead to the recruitment of freely diffusing receptors into the adhesion zone. This is a result of the equilibration of the chemical potential difference that emerges when cadherins become part of large agglomerates of trans bonds. These cooperative effects lead to a significant enhancement in adhesion when cadherins are mobile and diffuse on the SLB compared with when they are immobile, quantitatively matching the experiments. This comprehensive model sheds light on the complex coupling between force-sensitive cadherin reaction kinetics and membrane mechanics during spreading of GUVs.