The manifold roles of sialic acid for the biological functions of endothelial glycoproteins

Abstract

Vascular endothelia are covered with a dense glycocalix that is heavily sialylated. Sialylation of vascular glycoconjugates is involved in the regulation of cell–cell interactions, be it among endothelial cells at cell junctions or between endothelial and blood-borne cells. It also plays important roles in modulating the binding of soluble ligands and the signaling by vascular receptors. Here, we provide an overview over the sialylation-function relationships of glycoproteins expressed in the blood and lymphatic vasculature. We first describe cellular interactions in which sialic acid contributes in a stereospecific manner to glycan epitopes recognized by glycan-binding proteins. Our major focus is however on the rarely discussed examples of vascular glycoproteins whose biological functions are modulated by sialylation through other mechanisms.

ST6Gal-I–mediated sialylation of the epidermal growth factor receptor modulates cell mechanics and enhances invasion

“…Molecular dynamics (MD) simulations investigating glycosylation of key Asn residues on EGFR dimerization align with this “negative binding cooperativity” model ( 110 ). Sialylation adds an additional level of regulation, which potentially drives structural changes and sustained activation of downstream signaling through retention of EGFR at the cell surface ( 111 ).…”

Glycans as Targets for Drug Delivery in Cancer

“…One of the main terminal modifications of glycans is the addition of a negatively charged acid (Neu5Ac) to glycoproteins and GSLs, contributing to their biophysical and biological functions. Sialylation of glycoproteins plays key roles in the blood and lymphatic vasculature, being essential for cell–cell and glycoprotein–protein interactions [ 33 , 34 , 35 ]. The SLe x and SLe a isomers mediate, under physiological conditions, the binding of circulating leukocytes to cell surface selectins expressed on activated endothelial cells during immune responses [ 36 ].…”

Sialoglycans on lymphatic endothelial cells augment interactions with Siglec‐1 (CD169) of lymph node macrophages

“…SCS floor LEC and SCS ceiling LEC represented the two most distant cell clusters in nearest neighbor alignments 8 and unsupervised clustering, 7 Interestingly, MadCAM1 and Glycam-1 are among those endothelial glycoproteins of the HEV that express the L-selectin ligands sialyl Lewis X and 6-O-sulfo sialyl Lewis X (sialic acid α2-3Galβ1-4(Fucα1-3(SO 3 -6)) GlcNAc) collectively termed PNAd. [9][10][11]51 It appears that their glycosylation differs between the HEV and SCS floor LEC. HEV, but not the SCS floor LEC, were stained by the MECA-79 antibody against PNAd.…”

“…7,8 Many of the endothelial marker proteins are glycosylated. 9 The expressed glycans can be directly recognized by glycan-binding proteins (lectins), and influence protein structure and functions. Thus, they have a major impact on molecular and cellular interactions.…”