Regulation of Endothelial Cell Barrier Function by Antibody-driven Affinity Modulation of Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1)

Abstract

Background: PECAM-1 participates in adhesion and signaling in blood and vascular cells. Results:The adhesive properties of PECAM-1 in both cellular and artificial membranes can be regulated. Conclusion:The binding affinity of PECAM-1 can be regulated by engagement of membrane-proximal Ig domain 6. Significance: Modulating the adhesive properties of PECAM-1 offers possibility to control endothelial cell migration and barrier function in vascular permeability disorders.

Local VE-cadherin mechanotransduction triggers long-ranged remodeling of endothelial monolayers

“…Interestingly, anti-PECAM-1 antibodies against different domains also reportedly have different effects on PECAM-1 affinity and adhesion (Mei et al, 2014), consistent with the allosteric regulation of PECAM-1 binding. The behavior of both proteins is analogous to that of integrins, which require specific ligation or conformation-selective antibodies for activation (Hynes, 2002).…”

Structural basis for PECAM-1 homophilic binding

“…74 Future planned studies should allow us to examine the mechanism by which other regions of the extracellular domain are able to affect the affinity modulation of PECAM-1 leading to adhesion strengthening of endothelial cell-cell junctions. 26 Sequence alignment (Figure 2) shows that both IgD1 and IgD2 are well conserved evolutionarily, especially in regions that form b strands, suggesting that the overall structural folds observed in For personal use only. on May 12, 2018.…”

“…24,25 Finally, studies using PECAM-1-containing nanodiscs and intact endothelial cells suggest that the affinity of PECAM-1/PECAM-1 homophilic interactions may be additionally regulated by heterophilic ligands that bind membrane-proximal PECAM-1 IgD6. 26 Given the importance of PECAM-1-mediated homophilic interactions in mediating each of these cell physiological events, and to reveal the nature and orientation of the PECAM-1-PECAM-1 homophilicbinding interface, we undertook studies aimed at determining the crystal structure of the homophilic-binding domain of PECAM-1. Our results yield novel insights and suggest a model for the molecular nature of the interactions that PECAM-1 forms during assembly of endothelial cell intercellular junctions.…”

The Role of Sialylated Glycans in Human Platelet Endothelial Cell Adhesion Molecule 1 (PECAM-1)-mediated Trans Homophilic Interactions and Endothelial Cell Barrier Function

“…PECAM-1 has been shown in a number of laboratories to be an important contributor to the maintenance of the vascular permeability barrier as well as to its restoration following thrombotic or inflammatory insult (15,16,52,53). The ability of PECAM-1 to localize to, and concentrate at, cell-cell junctions, where it carries out this function, is completely dependent on its ability to form trans PECAM-1/PECAM-1 homophilic interactions, an adhesive property of the PECAM-1 extracellular domain that was first proposed more than 25 years ago (54), shown to be due to diffusion trapping of the receptor at cell-cell junctions 10 years later (9) and most recently found to support endothelial cell junctional integrity in a potentially regulatable manner (17,55). Interestingly, Cioffi et al (56) have shown recently that not only are sialic acids an important determinant of endothelial barrier integrity but that, although the arterial endothelium is likely to display both ␣2,3 and ␣2,6 sialic acid residues, the cell surface receptors of microvascular endothelial cells are primarily ␣2,3-sialylated.…”