| Functions of the proteoglycans
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| Bottlebrushes, silly putty and reinforced concrete
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| Proteoglycans are found in association with most tissues and cells. One of their major roles is to provide structural support to tissues, especially cartilage and connective tissue. In cartilage, large aggregates, composed of chondroitin sulfate and keratan sulfate chains linked to their core proteins, are noncovalently associated with hyaluronic acid via link proteins, forming a jelly-like matrix in which the collagen fibers are embedded. This macromolecule of macromolecules, a 'bottlebrush' structure known as aggrecan (Fig. 27.9), provides both rigidity and stability to connective tissue.
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| Figure 27.9 Structure of aggrecan. Associations between proteoglycans and hyaluronic acid form an aggrecan structure in the extracellular matrix (ECM). The extension of this structure yields a three-dimensional array of proteoglycans bound to hyaluronic acid, which creates a stiff matrix or 'bottlebrush' structure in which collagen and other ECM components are embedded. |
| Because of their negative charge, the GAGs bind large amounts of monovalent and divalent cations: a cartilage proteoglycan molecule of 2 ×106 Da would have an aggregate negative charge of about 10 000. The maintenance of
electrical neutrality consequently requires a high concentration of counterions. These ions draw water into the ECM, causing swelling and stiffening of the matrix, the result of tension between osmotic forces and binding interactions between proteoglycans and collagen. The structure and hydration of the ECM allows for a degree of rigidity, combined with flexibility and compressibility, enabling the tissue to withstand torsion and shock. The hyaluronic acid-proteoglycan-collagen aggregates in vertebral and articular disks have some of the viscoelastic properties of 'silly putty', bounce plus resilience, cushioning the impact between bones. These discs compress during the course of the day, expand elastically during the course of night, and deform gradually with age.
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| The overall structure of cartilage can be likened to that of the vertical reinforced-concrete slabs poured during the construction of large buildings, in which steel rods (collagen fibers) are embedded in an amorphous layer of cement (the proteoglycan aggregates). Collagen stabilizes the network of proteoglycans in cartilage in much the same way that the reinforcing rods in the concrete provide structural strength for the cement walls. The structure of earthquake-resistant buildings, like the ECM, provides a balance between integrity and flexibility.
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Although the amounts involved are low compared with those in skin and cartilage, organs such as the liver, brain, or kidney also contain a variety of proteoglycans:
- hepatocytes: heparan sulfate is the principal GAG; it is present both intracellularly and on the cell surface of the hepatocyte, and the attachment of hepatocytes to their substratum in cell culture is mediated, at least in part, by this proteoglycan;
- kidney: changes in both the collagen and proteoglycan content of the renal basement membrane are associated with diabetic renal disease. In this case, the change in
structure and charge of the proteoglycans aggregate, known as perlecan, is associated with a change in the filtration selectivity of the glomerulus;
- cornea: two populations of proteoglycans have been identified in the cornea, one containing keratan sulfate and the other dermatan sulfate. These molecules have a much smaller hydrodynamic size than the large cartilage proteoglycans, which may be required for interaction of the corneal proteoglycans with the tightly packed and oriented collagen fibers in this transparent tissue. Corneal clouding in macular corneal dystrophy is associated with undersulfation of keratan sulfate I proteoglycan.
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| Other complex glycan aggregates with subtle variations in core protein structure and glycan composition are distributed in intracellular compartments, plasma membranes and in the extracellular space in a tissue-specific manner and vary with age and disease.
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Some proteoglycans or GAGs, especially heparin and heparan sulfate, probably have important physiologic roles in binding proteins or other macromolecules:
- mast cells (granulated cells involved in the inflammatory response): heparin is believed to function as an intracellular binding site maintaining proteinases in secretory granules in an inactive state.
- the vascular wall: proteoglycans are involved with the binding of proteins and enzymes, such as low-density lipoprotein and lipoprotein lipase, to the vascular wall (see Chapter 17). They may also inhibit clot formation on the vascular wall by surface activation of antithrombin III (Chapter 6).
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