A putative structural mechanism underlying the antithetic effect of homologous RND1 and RhoD GTPases in mammalian plexin regulation
- Peking University, China
- Beijing Computational Science Research Center, China
- University of Texas Southwest Medical Center, United States
- University of Texas Southwestern Medical Center, United States
- Antidote Health Foundation, United States
Abstract
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.
Data availability
Diffraction data have been deposited in PDB under the accession code 7KDC.Simulation data have been deposited in ZONODO database.
Article and author information
Author details
Funding
National Natural Science Foundation of China (21806004)
- Yanyan Liu
NSAF Joint Fund (U1430237)
- Yanyan Liu
National Institutes of Health (R35GM130289)
- Xuewu Zhang
Welch Foundation (I-1702)
- Chen Song
National Natural Science Foundation of China (21873006)
- Chen Song
National Natural Science Foundation of China (32071251)
- Chen Song
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Aaron Frank, University of Michigan, United States
Version history
- Received: October 24, 2020
- Accepted: June 10, 2021
- Accepted Manuscript published: June 11, 2021 (version 1)
- Version of Record published: June 22, 2021 (version 2)
Copyright
© 2021, Liu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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A putative structural mechanism underlying the antithetic effect of homologous RND1 and RhoD GTPases in mammalian plexin regulation
eLife 10:e64304.
https://doi.org/10.7554/eLife.64304
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