Binding cooperativity of membrane adhesion receptors

TL;DR

This paper investigates how membrane flexibility influences receptor-ligand binding, revealing that membrane roughness causes cooperative binding effects that impact the measurement of binding affinities.

Contribution

It demonstrates that membrane flexibility induces cooperative binding, challenging the assumption of linearity in binding affinity measurements for membrane-anchored molecules.

Findings

Flexible membranes cause cooperative binding of receptors and ligands.

The area concentration of bonds scales with the square of unbound molecule concentrations.

This cooperativity explains discrepancies in experimental binding affinity measurements.

Abstract

The adhesion of cells is mediated by receptors and ligands anchored in apposing membranes. A central question is how to characterize the binding affinity of these membrane-anchored molecules. For soluble molecules, the binding affinity is typically quantified by the binding equilibrium constant K3D in the linear relation [RL] = K3D [R][L] between the volume concentration [RL] of bound complexes and the volume concentrations [R] and [L] of unbound molecules. For membrane-anchored molecules, it is often assumed by analogy that the area concentration of bound complexes [RL] is proportional to the product [R][L] of the area concentrations for the unbound receptor and ligand molecules. We show here (i) that this analogy is only valid for two planar membranes immobilized on rigid surfaces, and (ii) that the thermal roughness of flexible membranes leads to cooperative binding of receptors and ligands. In the case of flexible membranes, the area concentration [RL] of receptor-ligand bonds is proportional to the square of [R][L] for typical lengths and concentrations of receptors and ligands in cell adhesion zones. The cooperative binding helps to understand why different experimental methods for measuring the binding affinity of membrane-anchored molecules have led to values differing by several orders of magnitude.