How the biomimetic assembly of membrane receptors into multivalent domains is regulated by a small ligand.

Anna Grochmal,Ben Woods,Salvador Tomas,Manuel Perez-Soto,Lilia Milanesi

doi:10.1039/d1sc01598b

Abstract

In living cells, communication requires the action of membrane receptors that are activated following very small environmental changes. A binary all-or-nothing behavior follows, making the organism extremely efficient at responding to specific stimuli. Using a minimal system composed of lipid vesicles, chemical models of a membrane receptor and their ligands, we show that bio-mimetic ON/OFF assembly of high avidity, multivalent domains is triggered by small temperature changes. Moreover, the intensity of the ON signal at the onset of the switch is modulated by the presence of small, weakly binding divalent ligands, reminiscent of the action of primary messengers in biological systems. Based on the analysis of spectroscopic data, we develop a mathematical model that rigorously describes the temperature-dependent switching of the membrane receptor assembly and ligand binding. From this we derive an equation that predicts the intensity of the modulation of the ON signal by the ligand-messenger as a function of the pairwise binding parameters, the number of binding sites that it features and the concentration. The behavior of our system, and the model derived, highlight the usefulness of weakly binding ligands in the regulation of membrane receptors and the pitfalls inherent to their binding promiscuity, such as non-specific binding to the membrane. Our model, and the equations derived from it, offer a valuable tool for the study of membrane receptors in both biological and biomimetic settings. The latter can be exploited to program membrane receptor avidity on sensing vesicles, create hierarchical protocell tissues or develop highly specific drug delivery vehicles.

Highlights

Receptors located on the cell membrane bind to ligands present in solution or displayed on other surfaces, and play a central role in cell adhesion and communication processes.[1,2,3] The regulation of receptors involves the participation of complex machinery, tasked with the detection of the appropriate environmental changes and activation of the receptors when the level of a given stimulus reaches a critical threshold.[2]
Simple models of a cell membrane, in the form of lipid vesicles equipped with minimal synthetic membrane receptors and ligands, have shown that the lateral assembly of receptors enhances both binding to ligands
We have shown that increasing the in-membrane concentration of 1Ch in lipid vesicles leads to a red-shi of the Soret band of the porphyrin moieties UV-visible spectrum, characteristic of J-aggregates.[17]

Summary

Introduction

Receptors located on the cell membrane bind to ligands present in solution or displayed on other surfaces, and play a central role in cell adhesion and communication processes.[1,2,3] The regulation of receptors involves the participation of complex machinery, tasked with the detection of the appropriate environmental changes and activation of the receptors (for example, by recruiting them at the point of interaction into platforms of high avidity) when the level of a given stimulus reaches a critical threshold.[2]. We rigorously characterized the mutual modulation between the lateral assembly of membrane receptors and the binding of ligands in solution.[7,16] The mathematical model we developed allowed us to quantify the enhancement of binding due to the formation of multivalent receptor clusters and relate it to a multivalent effect. In the present work we show that changes in the membrane phase (from liquid disordered to gel) lead to an ON/OFF bimodal response in the assembly of the membrane embedded receptor

Objectives

Results

Conclusion