Insights into intercellular receptor-ligand binding kinetics in cell communication

Abstract

Cell-cell communication is crucial for cells to sense, respond and adapt to environmental cues and stimuli. The intercellular communication process, which involves multiple length scales, is mediated by the specific binding of membrane-anchored receptors and ligands. Gaining insight into two-dimensional receptor-ligand binding kinetics is of great significance for understanding numerous physiological and pathological processes, and stimulating new strategies in drug design and discovery. To this end, extensive studies have been performed to illuminate the underlying mechanisms that control intercellular receptor-ligand binding kinetics via experiment, theoretical analysis and numerical simulation. It has been well established that the cellular microenvironment where the receptor-ligand interaction occurs plays a vital role. In this review, we focus on the advances regarding the regulatory effects of three factors including 1) protein-membrane interaction, 2) biomechanical force, and 3) bioelectric microenvironment to summarize the relevant experimental observations, underlying mechanisms, as well as their biomedical significances and applications. Meanwhile, we introduce modeling methods together with experiment technologies developed for dealing with issues at different scales. We also outline future directions to advance the field and highlight that building up systematic understandings for the coupling effects of these regulatory factors can greatly help pharmaceutical development.

Keywords: bioelectric microenvironment; biomechanical force; cell communication; intercellular receptor-ligand binding kinetics; protein-membrane interaction.

FIGURE 1

(A) Two fluctuating membranes adhering via specific binding of transmembrane (light blue) and lipid-anchored (light purple) receptor and ligand proteins. Both the thermal shape fluctuations of membranes, which change the average membrane separation and relative membrane roughness, and the anchoring energy affect the receptor-ligand binding kinetics. (B) Wedge-shaped transmembrane proteins bend their associated membranes to induce membrane curvature. The local curvatures induced by receptor and ligand affect their binding kinetics by 1) altering the local separation and relative roughness of the two apposing membranes and 2) causing protein-protein cis-repulsion on each membrane. (C) Preferential partitioning of membrane-anchored receptors and ligands in the lipid rafts (light green) enhances the binding affinity of those proteins, which can be partially attributed to the entropy gain of the membranes resulting from raft-induced protein aggregation. (D) Adhering membranes linked via two types of membrane-anchored receptors and ligands with different lengths in the presence of glycocalyx (dark green). The difference in lengths between the shorter and longer receptor-ligand complexes, on the one hand, forms a steric barrier for the complex formation, on the other hand, facilitates protein aggregation to enhance binding. These two competing effects are additionally regulated by the presence of glycocalyx.

FIGURE 2

Biomechanical regulations of membrane receptors’ functions revealed by SMFS techniques. (A) AFM dissecting biomechanical regulations on the interaction of P-selectin and PSGL-1 [Adapted from Ref. (An et al., 2017)]. (B) Dual BFP system revealing biomechanical-chemical coupling signal transduction circuits on platelet. (C) Fluorescent imaging integrated BFP system digitalizing the triggering threshold of TCR [Adapted from Ref. (An et al., 2017)].

FIGURE 3

Bioelectric cues surrounding TCRs on T cell membranes. The bioelectric cues that potentially affect TCR functions include membrane potential, ion flux and anionic lipids in the inner cell membranes. Ca²⁺ flux induced by TCR triggering impedes the electrostatic interaction between anionic lipids and the basic rich regions in CD3 tails.