A computational study for understanding the impact of p120-catenin on the cis-dimerization of cadherin  

作　　者：Zhaoqian Su Vinh H.Vu Deborah ELeckband Yinghao Wu 

机构地区：[1]Department of Systems and Computational Biology,Albert Einstein College of Medicine,1300 Morris Park Avenue,Bronx,NY10461,USA [2]Department of Biochemistry and University of linois,Urbana-Champaign,Urbana,IL 61801,USA [3]Department of Chemical and Biomolecular Engineering,University of llinois,Urbana-Champaign,Urbana,IL 61801,USA

出　　处：《Journal of Molecular Cell Biology》2023年第9期14-24,共11页分子细胞生物学报（英文版）

基　　金：supported by the National Institutes of Health under grant number 1R01GM117104;supported by the National Institutes of Health under grant numbers R01GM120238 and R01GM122804;supported by a start-up grant from Albert Einstein College of Medicine.Computational support was provided by Albert Einstein College of Medicine High Performance Computing Center and by the National Science Foundation through the Extreme Science and Engineering Discovery Environment(XSEDE)undergrant numberTG-MCB200014.

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(p120ctn)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 p120ctn.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 p120ctn can increase the probability of lateral interactions between cadherins on the cell surface.These results suggest that p120ctn could allosterically regulate the cis-dimerization of cadherin through two mechanisms.First,p120ctn controls the extracellular conformational dynamics of cadherin.Second,p120ctn 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.

关 键 词：multiscale modeling inside-out signaling molecular dynamics simulations cadherin-mediated cell adhesion 

分 类 号：Q51[生物学—生物化学]