Lipid-dependent conformational landscape of the ErbB2 growth factor receptor dimers

Abstract

Altered lipid metabolism has been linked to cancer development and progression. Several roles have been attributed to the increased saturation and length of lipid acyl tails observed in tumors, but its effect on signaling receptors is still emerging. In this work, we have analyzed the lipid dependence of the ErbB2 growth factor receptor dimerization that plays an important role in the pathogenesis of breast cancer. We have performed coarse-grain ensemble molecular dynamics simulations to comprehensively sample the ErbB2 monomer-dimer association. Our results indicate a dynamic dimer state with a complex conformational landscape that is modulated with increasing lipid tail length. We resolve the native N-terminal "active" and C-terminal "inactive" conformations in all membrane compositions. However, the relative population of the N-terminal and C-terminal conformers is dependent on length of the saturated lipid tails. In short-tail membranes, additional non-specific dimers are observed which are reduced or absent in long-tailed bilayers. Our results indicate that the relative population as well as the structure of the dimer state is modulated by membrane composition. We have correlated these differences to local perturbations of the membrane around the receptor. Our work is an important step in characterizing ErbB dimers in healthy and diseased states and emphasize the importance of sampling lipid dynamics in understanding receptor association.

Lipid-mediated Association of the Slg1 Transmembrane Domains in Yeast Plasma Membranes

“…The ordering effect was stronger for membranes with already higher order parameter. This is in agreement with stronger variation of membrane thickness around ErbB2 dimers in DPPC as compared to DLPC bilayers [24]. We speculate that this represents a self-reinforcing mechanism for dimer formation, since the dimerization is more preferable for systems with higher order.…”

“…The molecular mechanism for this different behavior still needs to be revealed. The modulation of the structure of dimers by different membrane environments, comprised of only one lipid type, has also been reported for ErbB2 TMDs [24]. Interestingly, we also showed that the free energy of dimerization for POPC-Erg and DOPC systems without PS is slightly lower for LH configurations as compared to RH ones, whereas for DOPC systems with PS the opposite holds.…”

“…Experimentally, increased thickness of model membranes through longer acyl chains or addition of cholesterol promotes the self-association of TMDs [8]. Other examples of the effect of non-specific protein-lipid interactions for TMD association, including both simulations experiments, are also present: dimerization of bitopic TMDs is affected by the length and degree of saturation of lipids acyl chains [15, 23, 24] and charge [25] in the surrounding lipids of the bilayer. MD simulations have also inspected the comparative effects of lipids decoupling from TMD dimers [26, 27].…”

“…A reduction in membrane perturbation in terms of membrane thickness and order has also been observed upon helix association [29]. Local membrane thickness variations have been also observed around dimers in model membranes with different lipid compositions [24].…”

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

“…Several studies also suggested that the lipid environment may control the mode of dimerization. 14,17,23 As a further examination of the convergence of the dimer binding modes, we calculated the free energy of binding for EphA1, Caution needs to be exercised when comparing ab initio predictions, MD simulation results or even structures derived from experiments. First, the comparison needs to be performed for the same TM peptide or protein construct, as well as for the same membrane composition.…”