摘要A prototype of cross-membrane signal transduction is that extracellular binding of cell surface receptors to their ligands induces intracellular signalling cascades.However,much less is known about the process in the opposite direction,called inside-out signalling.Recent studies show that it plays a more important role in regulating the functions of many cell surface receptors than we used to think.In particular,in cadherin-mediated cell adhesion,recent experiments indicate that intracellular binding of the scaffold protein p120-catenin can promote extracellular clustering of cadherin and alter its adhesive function.The underlying mechanism,however,is not well understood.To explore possible mechanisms,we designed a new multiscale simulation procedure.Using all-atom molecular dynamics simulations,we found that the conformational dynamics of the cadherin extracellular region can be altered by the intracellular binding of p120-catenin.More intriguingly,by integrating all-atom simulation results into coarse-grained random sampling,we showed that the altered conformational dynamics of cadherin caused by the binding of p120-catenin can increase the probability of lateral interactions between cadherins on the cell surface.These results suggest that p120-catenin could allosterically regulate the cis-dimerization of cadherin through two mechanisms.First,p120-catenin controls the extracellular conformational dynamics of cadherin.Second,p120-catenin oligomerization can further promote cadherin clustering.Therefore,our study provides a mechanistic foundation for the inside-out signalling in cadherin-mediated cell adhesion,while the computational framework can be generally applied to other cross-membrane signal transduction systems.