Cell migration is guided by signals from transmembrane receptors, notably plexins and Eph receptors, which integrate protein-protein and protein-membrane interactions to control cytoskeletal dynamics. Recent biophysical and computational studies have provided structural and mechanistic insight into how these large receptors orchestrate signaling. Molecular dynamics simulations revealed that the Rho GTPase binding domain (RBD) of plexins engages Rac1 and Rnd1 with distinct isoform-specific contact dynamics, highlighting how subtle changes modulate signaling outcomes (Zhang and Buck, 2017). Downstream, the Rap1b GTPase substrate is regulated allosterically: conformational fluctuations from the transmembrane and juxtamembrane domains propagate into the intracellular GAP module (Li et al., 2021; Bhattarai et al., 2025). Coarse-grained and atomistic simulations support this allosteric view showing how the plexin transmembrane helix samples alternative dimeric states that can tune catalytic activity (Sahoo et al., 2023). For EphA2, complementary studies demonstrate how the membrane environment itself directly regulates receptor activation. Biophysical measurements and simulations revealed that conformational “clamping” by anionic lipids promotes receptor activation (Westerfield et al., 2021). Recent work extends this principle: phosphatidylinositol-(4,5)-bisphosphate PI(4,5)P 2 organizes EphA2 together with EGFR into lipid-dependent complexes (Singh et al., 2024), while cholesterol modulates EphA2 dimerization and conformational switching (Sahoo et al., 2025). These studies and also work on the intracellular region of EphA2 (Shrestha et al., 2025) underscore the dynamic role of the membrane in shaping receptor architecture and cross-talk.
Matthias Buck (Sun,) studied this question.