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

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外文摘要：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.

外文关键词：

multiscale modelinginside-out signalingmolecular dynamics simulationscadherin-mediated cell adhesion

作者：

Zhaoqian Su、Vinh H.Vu、Deborah E.Leckband、Yinghao Wu

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作者单位：

Department of Systems and Computational Biology,Albert Einstein College of Medicine,1300 Morris Park Avenue,Bronx,NY 10461,USA

Department of Biochemistry and University of Illinois,Urbana-Champaign,Urbana,IL 61801,USA

Department of Chemical and Biomolecular Engineering,University of Illinois,Urbana-Champaign,Urbana,IL 61801,USA

基金：

National Institutes of HealthNational Institutes of HealthNational Institutes of HealthAlbert Einstein College of Medicine High Performance Computing CenterNational Science Foundation through the Extreme Science and Engineering Discovery Environment(XSEDE)

项目编号：

number 1R01GM117104numbers R01GM120238R01GM122804number TG-MCB200014

出版年：

2023

DOI：

10.1093/jmcb/mjad055

分子细胞生物学报(英文版)

中国科学院上海生命科学研究院,生物化学与细胞生物学研究所,中国细胞生物学学会

分子细胞生物学报(英文版)

CSTPCDCSCD

影响因子：0.595

ISSN：1673-520X

年,卷(期)：2023.(9)

参考文献量65