Polysaccharides:- Proteoglycans Are Glycosaminoglycan-Containing Macromolecules of the Cell Surface and Extracellular Matrix

Mammalian cells can produce at least 30 types of molecules that are members of the proteoglycan superfamily. These molecules act as tissue organizers, influence the development of specialized tissues, mediate the activities of various growth factors, and regulate the extra cellular assembly of collagen fibrils. The basic proteoglycan unit consists of a “core protein” with covalently attached glycosaminoglycan(s). For example, the sheet like extracellular matrix (basal lamina) that separates organized groups of cells contains a family of core proteins (Mr 20,000 to 40,000), each with several covalently attached heparan sulfate chains. (Heparan sulfate is structurally similar to heparin but has a lower density of sulfate esters.) The point of attachment is commonly a Ser residue, to which the glycosaminoglycan is joined through a trisaccharide bridge (Fig. 7–26). The Ser residue is generally in the sequence –Ser–Gly–X–Gly (where X is any amino acid residue), although not every protein with this sequence has an attached glycosaminoglycan. Many proteoglycans are secreted into the extracellular matrix, but some are integral membrane proteins (see Fig. 11–7). For example, syndecan core protein (Mr 56,000) has a single transmembrane domain and an extracellular domain bearing three chains of heparan sulfate and two of chondroitin sulfate, each at tached to a Ser residue (Fig. 7–27a). There are at least four members of the syndecan family in mammals. Another family of core proteins is the glypicans, with six members. These proteins are attached to the membrane by a lipid anchor, a derivative of the membrane lipid phosphatidylinositol.

FIGURE 7–26 Proteoglycan structure, showing the trisaccharide bridge. A typical trisaccharide linker (blue) connects a glycosamino glycan—in this case chondroitin sulfate (orange)—to a Ser residue (red) in the core protein. The xylose residue at the reducing end of the linker is joined by its anomeric carbon to the hydroxyl of the Ser residue.

The heparan sulfate moieties in proteoglycans bind a variety of extracellular ligands and thereby modulate the ligands’ interaction with specific receptors of the cell surface. Detailed examination of the glycan moiety of proteoglycans has revealed a sequence heterogeneity that is not random; some domains (typically 3 to 8 di saccharide units long) differ from neighboring domains in sequence and in ability to bind to specific proteins. Heparan sulfate, for example, is initially synthesized as a long polymer (50 to 200 disaccharide units) of alternating N-acetylglucosamine (GlcNAc) and glucuronic acid (GlcA) residues. This simple chain is acted on by a series of enzymes that introduce alterations in specific regions. First, an N-deacetylase: N-sulfotransferase re places some acetyl groups of GlcNAc residues with sulfates, creating clusters of N-sulfated glucosamine (GlcN) residues. These clusters then attract enzymes that carry out further modifications: an epimerase converts GlcA to IdoA; sulfotransferases then create sulfate esters at the C-2 hydroxyl of IdoA and the C-6 hydroxyl of N-sulfated GlcN, but only in regions that already have N-sulfated GlcN residues. The result is a polymer in which highly sulfated domains (S domains) alternate with domains having unmodified GlcNAc and GlcA residues (N-acetylated, or NA, domains) (Fig. 7–27b). The exact pattern of sulfation in the S domain differs in different proteoglycans; given the number of possible modifications of the GlcNAc–IdoA dimer, at least 32 different disaccharide units are possible. Furthermore, the same core protein can display different heparan sulfate structures when synthesized in different cell types. The S domains bind specifically to extracellular proteins and signaling molecules to alter their activities. The change in activity may result from a conformational change in the protein that is induced by the binding (Fig. 7–28a), or it may be due to the ability of adjacent do mains of heparan sulfate to bind to two different proteins, bringing them into close proximity and enhancing protein-protein interactions (Fig. 7–28b). A third general mechanism of action is the binding of extracellular signal molecules (growth factors, for example) to heparan sulfate, which increases their local concentrations and enhances their interaction with growth factor receptors in the cell surface; in this case, the heparan sulfate acts as a coreceptor (Fig. 7–28c). For example, fibroblast growth factor (FGF), an extracellular protein signal that stimulates cell division, first binds to heparan sulfate moieties of syndecan molecules in the target cell’s plasma membrane. Syndecan presents FGF to the FGF plasma membrane receptor, and only then can FGF interact productively with its receptor to trigger cell division. Finally, the S domains interact—electrostatically and otherwise—with a variety of soluble molecules outside the cell, maintaining high local concentrations at the cell surface (Fig. 7–28d). The importance of correctly synthesizing sulfated domains in heparan sulfate is demonstrated in “knockout” mice that lack the enzyme that places sulfates at the C-2 hydroxyl of IdoA. Such animals are born without kidneys and with very severe abnormalities in development of the skeleton and eyes. Some proteoglycans can form proteoglycan aggregates, enormous supramolecular assemblies of many core proteins all bound to a single molecule of hyaluronate. Aggrecan core protein (Mr ~250,000) has multiple chains of chondroitin sulfate and keratan sulfate, joined to Ser residues in the core protein through trisaccharide linkers, to give an aggrecan monomer of Mr ~2 x10⁶. When a hundred or more of these “decorated” core proteins bind a single, extended molecule of hyaluronate (Fig. 7–29), the resulting proteoglycan aggregate (Mr>2 x 10⁸) and its associated water of hydration occupy a volume about equal to that of a bacterial cell! Aggrecan interacts strongly with collagen in the extracellular matrix of cartilage, contributing to the development and tensile strength of this connective tissue. Interwoven with these enormous extracellular proteoglycans are fibrous matrix proteins such as collagen, elastin, and fibronectin, forming a cross-linked mesh work that gives the whole extracellular matrix strength and resilience. Some of these proteins are multiadhe sive, a single protein having binding sites for several different matrix molecules. Fibronectin, for example, has separate domains that bind fibrin, heparan sulfate, collagen, and a family of plasma membrane proteins called integrins that mediate signaling between the cell interior and the extracellular matrix (see Fig. 11–24). Inte grins, in turn, have binding sites for a number of other extracellular macromolecules. The overall picture of cell-matrix interactions that emerges (Fig. 7–30) shows an array of interactions between cellular and extracellular molecules. These interactions serve not merely to anchor cells to the extracellular matrix but also to provide paths that direct the migration of cells in developing tissue and, through integrins, to convey information in both directions across the plasma membrane.

FIGURE 7–27 Proteoglycan structure of an integral membrane protein. (a) Schematic diagram of syndecan, a core protein of the plasma membrane. The amino-terminal domain on the extracellular surface of the membrane is covalently attached (by trisaccharide linkers such as those in Fig. 7–26) to three heparan sulfate chains and two chondroitin sulfate chains. Some core proteins (syndecans, as here) are anchored by a single transmembrane helix; others (glypicans), by a covalently attached membrane glycolipid. In a third class of core proteins, the protein is released into the extracellular space, where it forms part of the basement membrane. (b) Along a heparan sulfate chain, regions rich in sulfated sugars, the S domains (green), alternate with regions with chiefly unmodified residues of GlcNAc and GlcA, the NA domains (gray). One of the S domains is shown in more detail, revealing a high density of modified residues: GlcA, with a sulfate ester at C-6; and IdoA, with a sulfate ester at C-2. The exact pat tern of sulfation in the S domain differs among proteoglycans. Given all the possible modifications of the GlcNAc–IdoA dimer, at least 32 different disaccharide units are possible.

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مواضيع ذات صلة

Nucleic Acid Structure:- DNA Stores Genetic Information

Carbohydrates as Informational Molecules: The Sugar Code:- Lectin-Carbohydrate Interactions Are Very Strong and Highly Specific

Carbohydrates as Informational Molecules: The Sugar Code:- Lectins Are Proteins That Read the Sugar Code and Mediate Many Biological Processes

Polysaccharides:- Glycolipids and Lipopolysaccharides Are Membrane Components

Polysaccharides: - Glycoproteins Have Covalently Attached Oligosaccharides

Polysaccharides:- Glycosaminoglycans Are Heteropolysaccharides of the Extracellular Matrix

Polysaccharides:- Bacterial and Algal Cell Walls Contain Structural Hetero polysaccharides

Polysaccharides: -Steric Factors and Hydrogen Bonding Influence Homopolysaccharide Folding

Polysaccharides:- Some Homopolysaccharides Serve Structural Roles

Polysaccharides:- Some Homopolysaccharides Are Stored Forms of Fuel

Monosaccharides and Disaccharides:- Disaccharides Contain a Glycosidic Bond

Monosaccharides and Disaccharides:- Monosaccharides Are Reducing Agents