Interplay Between Receptor-Ligand Binding and Lipid Domain Formation Depends on the Mobility of Ligands in Cell-Substrate Adhesion.

Long Li,Yingfeng Shao,Huaping Wu,Fan Song,Xiaohuan Wang,Helong Wu

doi:10.3389/fmolb.2021.655662

Abstract

Cell-cell adhesion and the adhesion of cells to extracellular matrix are mediated by the specific binding of receptors on the cell membrane to their cognate ligands on the opposing surface. The adhesion receptors can exhibit affinity for nanoscale lipid clusters that form in the cell membrane. Experimental studies of such adhesion systems often involve a cell adhering either to a solid surface with immobile ligands or a supported lipid bilayer with mobile ligands. A central question in these cell-substrate adhesions is how the mobility of the ligands physically affects their binding to the adhesion receptors and thereby the behavior of the nanoscale lipid clusters associated with the receptors. Using a statistical mechanical model and Monte Carlo simulations for the adhesion of cells to substrates with ligands, we find that, for mobile ligands, binding to adhesion receptors can promote the formation of mesoscale lipid domains, which in turn enhances the receptor-ligand binding. However, in the case of immobile ligands, the receptor-ligand binding and the tendency for the nanoscale lipid clusters to further coalesce depend on the distribution of the ligands on the substrate. Our findings help to explain why different adhesion experiments for identifying the interplay between receptor-ligand binding and heterogeneities in cell membranes led to contradictory results.

Highlights

Cell-cell adhesion and the adhesion of cells to the extracellular matrix (ECM), mediated by the specific binding of receptors and ligands anchored to the apposing surfaces, governs numerous biological processes such as signal transduction, immune responses, cell locomotion, tissue formation, as well as cancer invasion and metastasis (Weikl and Lipowsky, 2004; Krobath et al, 2009; van der Merwe and Dushek, 2011; Benham-Pyle et al, 2015; Chang et al, 2020; Li and Song, 2020; Romani et al, 2021)
We’ve investigated cell-substrate adhesion mediated by the binding of cell adhesion receptors to ligands that are either anchored to a substrate-supported planar lipid bilayer or directly immobilized on the flat substrate by means of Monte Carlo (MC) simulations and mean field (MF) calculations based on a classical statistical mechanical model
We focused on how the ligand mobility plays a role in the interplay between the receptor-ligand binding and raft domain formation

Summary

INTRODUCTION

Cell-cell adhesion and the adhesion of cells to the extracellular matrix (ECM), mediated by the specific binding of receptors and ligands anchored to the apposing surfaces, governs numerous biological processes such as signal transduction, immune responses, cell locomotion, tissue formation, as well as cancer invasion and metastasis (Weikl and Lipowsky, 2004; Krobath et al, 2009; van der Merwe and Dushek, 2011; Benham-Pyle et al, 2015; Chang et al, 2020; Li and Song, 2020; Romani et al, 2021). Evani and Ramasubramanian (Evani and Ramasubramanian, 2016) observed that the adhesion of infected monocytes to the microchannels coated with E-selectin is enhanced due to the increased uniformity of lipid raft and CD44 distribution These studies raise the question of how the mobility of the ligands physically affects their binding to the cell adhesion receptors and thereby the behavior of the nanoscale lipid clusters associated with the receptors. The raft coalescence in turn facilitates the formation of additional receptor-ligand complexes due to the less loss in the configurational entropy of the membrane This suggests that the receptor-ligand binding and raft domain formation in cell-supported bilayer adhesion system are mutually beneficial. Our results show that for ligands uniformly or randomly immobilized on the substrate, the receptor-ligand binding disfavors the aggregation of rafts, whereas for ligands immobilized in the form of clusters on the substrate, receptor-ligand binding and raft aggregation can cooperate

MODEL AND METHODS

Adhesion of Cell Membrane to the Planar

Adhesion of Cell Membrane to the Substrate with Immobile Ligands

CONCLUSION