Understanding Periperal Membrane Protein Interactions | BPS Thematic Meeting

Understanding Peripheral Membrane Protein Interactions: Structure, Dynamics, Function and Therapy

Monday Speaker Abstracts

PLEXIN AND EPH RECEPTORS: THE VIEW FROM PROTEIN BIOPHYSICS ON PROTEIN-MEMBRANE INTERACTIONS Matthias Buck 1 ; Amita Sahoo 1 ; Pravesh Shrestha 1 ; Nisha Bhattarai 1 ; 1 Case Western Reserve University, Physiology and Biophysics, Cleveland, OH, USA 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 & 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.References: Bhattarai, N., Morrison, L., Gomes, AF., Sahoo, AR, Buck, M. (2025) Computation model predicts Rho GTPase function with the Plexin Transmembrane receptor GAP activity on Rap1b via dynamic allosteric changes Protein Science, bioRxiv https://doi.org/10.1101/2025.03.13.643120 Li, Z., Muller-Greven , J., Kim, S-J, & Buck, M. (2021) “Plexin-B1 GAP function is regulated in solution by a new inhibitory loop: Evidence for allostery in the receptor’s signaling mechanisms involving the juxtamembrane domain”. Cell. & Mol. Life Sciences 78:1101-1112. Sahoo, A., Souza, PCT., Meng,, Y., & Buck, M. (2023) “Transmembrane region dimer structures of Type 1 receptors readily sample alternate configurations: MD simulations using the Martini 3 coarse grained model compared to AlphaFold2 Multimer” Structure (Cell Press) 31:735-745.e2. Sahoo, AR., Bhattarai, N., Buck, M. (2025) Cholesterol-Dependent Dimerization and Conformational Dynamics of EphA2 Receptors: Insights from Coarse-Grained and All-Atom Simulations online at Structure 4/24/25 and online at bioRxiv https://doi.org/10.1101/2025.01.07.631553 Shrestha, P., Sahoo , A.R., Iannucci , M., Willard, , B. & Buck, M. (2025) Tyrosine phosphorylation and the inhibitory C-terminal SAM domain moderately affect transient interactions in a EphA2 cytoplasmic fragment in solution: A combined experimental and molecular modeling study. Prepublished at BIORXIV/2025/679228 and submitted to Proc.Natl.Acad.Sci. USA Singh, PK., Rybak, JA , Schuck, RJ , Sahoo, AR , Buck, M., Barrera, FN., Smith, AW. (2024) Phosphatidylinositol (4,5)- bisphosphate drives the formation of EGFR and EphA2 complexes. Science Adv. 10(49):eadl0649 Westerfield JM, Sahoo AR, Alves DS, Grau B, Cameron A, Maxwell M, Schuster JA, Souza PCT, Mingarro I, Buck M. & Barrera FN. (2021) “Conformational Clamping

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