Cell Surface Heparan Sulfate Proteoglycans: Selective Regulators of Ligand-Receptor Encounters

Abstract

Cell surface heparan sulfate proteoglycans (HSPGs), 1 substantially more abundant than most receptors, modulate encounters of extracellular protein ligands with their receptors by forming HSprotein complexes. Two gene families account for most cell surface HSPGs. Both consist of discrete core proteins covalently attached to two or three chains of HS, an N-and O-sulfated linear polysaccharide of repeating disaccharides containing N-acetylglucosamine (GlcNAc) and uronic acid (glucuronic acid (GlcA) or iduronic acid (IdoUA)). The syndecan family was the first discovered, which in mammals contains four gene products with distinctive extracellular domains (ectodomains) and highly conserved short cytoplasmic domains. These apparently extended proteins place the HS chains distal from the plasma membrane (1, 2). The syndecan family contrasts with the glypican family, which in mammals contains six gene products that are covalently linked to plasma membrane lipid by glycosylphosphatidylinositol anchor (1, 3). The glypican core proteins contain six invariant disulfide bonds, are likely to be globular, and place HS chains adjacent to the plasma membrane. Expression of both the syndecans and glypicans is extensively regulated during mouse embryogenesis and results in discrete adult expression patterns for each HSPG such that every adherent cell exhibits a distinct repertoire of cell surface HSPGs.Binding to HS chains is remarkably widespread among extracellular proteins, especially matrix proteins, proteases and their inhibitors, lipases, lipoproteins, growth factors and their binding proteins, cytokines, chemokines, collectins, and antimicrobial peptides. These proteins are involved in morphogenesis, tissue repair, energy balance, and host defense (Fig. 1). Additionally, numerous pathogens (e.g. herpes simplex virus, Neisseria, Plasmodium) bind to the cell surface via HS (4). Importantly, many of these ligand-HS interactions are essentially identical from Drosophila to the mouse, including those involved in generation of the basic metazoan body plan, e.g. dpp (bone morphogenetic proteins 2-4), wg (Wnt-1), and sog (chordin).Formation of the complexes can enhance or reduce receptor activation, often depending on the concentrations of ligand, receptor, and HSPG. The HS chains catalyze encounters between ligand and signaling receptor by bringing them together. Because binding to the HS chain reduces the dimensionality of this interaction from three (when the ligand is soluble) to two (when the ligand is bound to the HS chain), interaction could result from a localized increase in ligand concentration at optimal HS concentrations (5). However, at HS levels lower or higher than optimal, the effective ligand concentration for engaging the receptor will fall, potentially accounting for the bell-shaped activity curve typically seen experimentally when HSPG (or heparin) concentrations are varied. The curve may be concave or convex depending on whether ligand binding to the HSPG is inhibitory or stimulatory (6). Furthermore, the cytop...

Functional cloning and characterization of a UDP- glucuronic acid decarboxylase: The pathogenic fungus Cryptococcus neoformans elucidates UDP-xylose synthesis

“…In animals xylose links the glycosaminoglycans heparan sulfate and chondroitin sulfate to the serine residues of proteoglycan core proteins. Proteoglycans are central to physiological processes from hemostasis to cell migration and development (28)(29)(30) and to pathologic processes such as microbial adherence and invasion (10); the availability of UDP-GlcA decarboxylase sequence will facilitate investigation of these events. The cloning and expression of UDP-GlcA decarboxylase from C. neoformans therefore should contribute to a broad array of investigations, ranging from plant biology, protein expression, and fungal pathogenesis to mammalian cell biology.…”

Control of matrix metalloproteinase catalytic activity

“…Most of cell surface proteoglycans contain either heparan sulfate (HS) or chondroitin sulfate (CS) GAG chains. Proteoglycans interact with a wide variety of effector proteins, such as chemokines and growth factors, via their GAG chains to elicit various processes (Park et al, 2000), and their ability to control proteinase activity, particularly of serine proteinases, is a well established. For example, heparin, a mast cell GAG that is a more sulfated than HS, affects the activity of several coagulation cascade proteinases, such as antithrombin III, thrombin, and factor Xa (Capila and Linhardt, 2002;Conrad, 1998), as well as tryptase, chymase, and cathepsin B (Almeida et al, 2001;Alter et al, 1987;Hallgren et al, 2000;Pejler and Sadler, 1999).…”

Alpha C Protein of Group B Streptococcus Binds Host Cell Surface Glycosaminoglycan and Enters Cells by an Actin-dependent Mechanism

“…These molecules also mediate interaction between epithelial cells and numerous pathogens, including viruses (such as human immunodeficiency virus (10), herpes simplex virus (31), human papilloma virus (9), and parainfluenza 3 (7)), spirochetes (such as Borrelia burgdorferi (32)), parasites (such as Trypanosoma cruzi (8)), and bacteria (such as Neisseria gonorrhoeae (11) and Listeria monocytogenes (6)). In some cases, GAG serves as a co-receptor, modulating the interaction of an extracellular ligand with other host cell surface structures by altering ligand concentration, stability, or conformation, or by promoting ligand or receptor oligomerization (33). In particular, HSPGs may facilitate interactions between ligands and cell-surface integrins (34 -36).…”