13.3: Proteoglycans

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The protein component of proteoglycans are not as large as fibrillar collagens in general, but they often ll a massive volume because of heavy glycosylation. The sugars, many of which are sulfated or carboxylated, are hygroscopic to begin with, but being negatively charged, attract positive ions, which in turn brings in more water. Sugars attached to the core proteins are usually repeating disaccharide units such as chondroitin (d-Glucuronic acid and GalNAc), chondroitin sulfate, heparin (d-Glucuronic acid and GlcNAc by α/β1-4 bond), heparan sulfate, keratan sulfate (Galactose and GlcNAc), or hyaluronan (also called hyaluronic acid, composed of d-Glucuronic acid linked by β1-3 bond to GlcNAc).

Heparin, a hypersulfated form of heparan sulfate, is also used medically as an anticlotting drug. It does so not by preventing clots directly, but by activating antithrombin III, which inhibits clotting.

As with all glycoproteins, assembly of the GAGs occurs in the Golgi, but beyond that, mechanisms for control of the extent and length of the disaccharide polymer addition is unknown. Unlike collagens and most other ECM components, proteoglycans can either be secreted or membrane bound. In fact, of the membrane bound proteoglycans, some are actually transmembrane proteins (these are designated syndecans), while other are bound to the cell surface via glycosylphosphatidylinositol (GPI) anchor (glypicans). In addition to these three basic varieties of core proteins, proteoglycans exhibit extraordinary diversity in glycosylation, ranging from the addition of only a few sugars, to well over a hundred. Interestingly, the core protein for chondroitin sulfate proteoglycans in basal lamina of muscle can be a collagen (Type XV)!

Figure \(\PageIndex{4}\). Proteoglycans are composed of multiple glycosaminoglycans attached to a core protein. These core proteins are sometimes attached to a hyaluronic acid molecule. Negatively charged sugars, like chondroitin sulfate or heparan sulfate, are depicted in yellow. They attract positive ions and water, forming a hydration shell around the proteoglycan. This Figure depicts aggrecan, a cartilaginous aggregate of proteoglycans assembled on a hyaluronic acid core.

One of the paradoxes of proteoglycans is that they can function either as a substrate for cells to attach to, or due to the hydration shell, they can be very effective barriers to other cells as well. This is useful during development when there is a great deal of cell migration, and there needs to be ways to segregate cells both by attracting them and repelling them. Unfortunately, this can have deleterious consequences in some situations. For example, when the brain or spinal cord is injured, a glial scar is formed, and that scar contains a chondroitin sulfate proteoglycan. Unfortunately, this proteoglycan is an inhibitor of neural growth, which contributes to the prevention of neural regeneration, and for the unlucky patient, likely paralysis or worse depending on location and severity of the lesion.

On the other hand, there is also evidence (Rolls et al, PLoS Med. 5: e171, 2008) that the CSPG may be needed to activate microglia and macrophages to promote healing.