Computational Model of E-cadherin Clustering under Cortical Tension

Abstract

E-cadherins are adhesion proteins that play a critical role in the formation of cell-cell junctions for several physiological processes, including tissue development and homeostasis. The formation of E-cadherin clusters involves extracellular trans- and cis- associations between cadherin ectodomains and stabilization through intracellular coupling with the contractile actomyosin cortex. The dynamic remodeling of cell-cell junctions largely depends on cortical tension, but previous modeling frameworks did not incorporate this effect. In order to gain insights into the effects of cortical tension on the dynamic properties of E-cadherin clusters, here we developed a computational model based on Brownian dynamics. The model considers individual cadherins as explicit point particles undergoing cycles of lateral diffusion on two parallel surfaces that mimic the membrane of neighboring cells. E-cadherins transit between functional states, including monomers, X- and S- dimers, that are able to selectively bind and unbind other E-cadherins on the same and/or opposite surface(s), and associate with the actomyosin cytoskeleton to stabilize their interactions and transmit tension. Kinetic rates for binding and unbinding are taken from previous experimental measurements, with unbinding rates reproducing catch or slip bonds lifetimes, depending on the E-cadherin functional state. Results from the model show that cortical tension governs the fraction of E-cadherins in clusters and the distribution of cluster size. For low forces (below 10 pN), a large amount of small clusters form, including less than 5 E-cadherins each, with the majority of E-cadherins in clusters. At higher forces, the probability of forming fewer but larger clusters increases, with most E-cadherins not in clusters. These findings support the general idea of force-dependent reinforcement of cell-cell junctions and are consistent with differences in cluster sizes observed between apical and lateral junctions in epithelial tissues.