The glycocalyx promotes cooperative binding and clustering of adhesion receptors

Abstract

Cell adhesion plays a pivotal role in various biological processes, e.g., immune responses, cancer metastasis, and stem cell differentiation. The adhesion behaviors depend subtly on the binding kinetics of receptors and ligands restricted at the cell-substrate interfaces. Although much effort has been directed toward investigating the kinetics of adhesion molecules, the role of the glycocalyx, anchored on cell surfaces as an exterior layer, is still unclear. In this paper, we propose a theoretical approach to study the collective binding kinetics of a few and a large number of binders in the presence of the glycocalyx, representing the cases of initial and mature adhesions of cells, respectively. The analytical results are validated by finding good agreement with our Monte Carlo simulations. In the force loading case, the on-rate and affinity increase as more bonds form, whereas this cooperative effect is not observed in the displacement loading case. The increased thickness and stiffness of the glycocalyx tend to decrease the affinity for a few bonds, while they have less influence on the affinity for a large number of bonds. Moreover, for a flexible membrane with thermally-excited shape fluctuations, the glycocalyx is exhibited to promote the formation of bond clusters, mainly due to the cooperative binding of binders. This study helps to understand the cooperative kinetics of adhesion receptors under physiologically relevant loading conditions and sheds light on the novel role of the glycocalyx in cell adhesion.

Feeling Things Out: Bidirectional Signaling of the Cell–ECM Interface, Implications in the Mechanobiology of Cell Spreading, Migration, Proliferation, and Differentiation

“…Dynamically, a recent study found that in the presence of glycocalyx, the binding kinetics of nascent and mature focal adhesions is in good agreement with the Monte Carlo simulation (see below for an explanation of the Monte Carlo simulation). The study also indicated that higher thickness and rigidity of glycocalyx decreases binding affinity at the nascent adhesion site but does not affect mature adhesions, effectively remobilizing integrins from new, unstable adhesions into mature adhesions 87. Over the past half century, research into focal adhesion biology has provided a myriad of insights into its constituents, functions, and roles in pathology.…”

Atomistic fingerprint of hyaluronan–CD44 binding

“…Similar regulation has been observed with LYVE-1 [ 20 ], an HA receptor homologous to CD44. Furthermore, the high molecular weight HA has been shown to induce the aggregation of CD44 receptors, while low molecular weight HA seems to lack this ability [ 21 , 22 ].…”

Binding and segregation of proteins in membrane adhesion: theory, modeling, and simulations

“…Calculations and simulations with discretized elastic-membrane models indicate segregation of sterically repulsive proteins of length l r and receptor-ligand complexes with preferred local separation l 0 < l r if the concentration of the repulsive proteins exceeds the critical concentration c r k B T /κ ef (l r − l 0 ) 2 with a numerical prefactor c r [27]. The interplay of receptor-ligand binding and steric repulsion from glycocalyx proteins has also been investigated in models for the clustering of integrin receptors during cell adhesion [75,[134][135][136]. In addition, segregation of long and short bonds has been observed in experiments with reconstituted membranes that adhere via anchored DNA [137].…”