A putative structural mechanism underlying the antithetic effect of homologous RND1 and RhoD GTPases in mammalian plexin regulation

eLife

Yibing Shan¹  Pu Ke²  Yanyan Liu³  Chen Song⁴  Xuewu Zhang⁵  Yi-Chun Kuo⁵  Yuxiao Wang⁵ 

[1] Antidote Health Foundation for Cure of Cancer, New York, United States;Beijing Computational Science Research Center, Beijing, China;Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China;Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China;Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China;Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States;

关键词: plexin;    small GTPases;    membrane interaction;    protein simulation;    Human;   

DOI  :  10.7554/eLife.64304

来源: eLife Sciences Publications, Ltd

【 摘 要 】

Plexins are semaphorin receptors that play essential roles in mammalian neuronal axon guidance and in many other important mammalian biological processes. Plexin signaling depends on a semaphorin-induced dimerization mechanism and is modulated by small GTPases of the Rho family, of which RND1 serves as a plexin activator yet its close homolog RhoD an inhibitor. Using molecular dynamics (MD) simulations, we showed that RND1 reinforces the plexin dimerization interface, whereas RhoD destabilizes it due to their differential interaction with the cell membrane. Upon binding plexin at the Rho-GTPase-binding domain (RBD), RND1 and RhoD interact differently with the inner leaflet of the cell membrane and exert opposite effects on the dimerization interface via an allosteric network involving the RBD, RBD linkers, and a buttress segment adjacent to the dimerization interface. The differential membrane interaction is attributed to the fact that, unlike RND1, RhoD features a short C-terminal tail and a positively charged membrane interface.

【 授权许可】

CC BY