We assembled and simulated putative models including plexin A4 resepctively complexed with RND1 and RhoD, to investigate the structural mechanisms underlying RND1 as an activator and RhoD as an attenuator in plexin signaling. The models suggested that RND1 binding is compatible with the dimerization of plexin A4 while RhoD binding is likely disruptive to the dimerization. The models also showed two distinct modes of interactions of RND1 and RhoD with the membrane: RND1 interacts with the membrane loosely and its long C-terminal tail serves as a flexible tether to the membrane, whereas RhoD interacts with the membrane in a specific manner using a positively-charged membrane interface, which is absent in RND1. Importantly, with RhoD binding at the RBD, the buttress interaction with the dimerization helix in the plexin dimer is much reduced compared to that in the RND1-bound dimer, suggesting that RhoD weakens the buttress interaction with the dimerization helix and potentially destabilizes the plexin dimer. In summary, RhoD binding destabilizes the RBD with respect to the GAP domain, destabilizing the buttress segment with respect to the dimerization interface, and ultimately leads to destabilization of the dimer interface. In contrast, by the same RBD-centered route, RND1 binding helps stabilize the plexin dimer.