Linking sugars

Aggrecan core protein

▲ FIGURE 6-22 Structure of proteoglycan aggregate from cartilage. (a) Electron micrograph of an aggrecan aggregate from fetal bovine epiphyseal cartilage. Aggrecan core proteins are bound at =40-nm intervals to a molecule of hyaluronan. (b) Schematic representation of an aggrecan monomer bound to hyaluronan. In aggrecan, both keratan sulfate and chondroitin sulfate chains are attached to the core protein. The N-terminal domain of the core protein binds noncovalently to a hyaluronan molecule. Binding is facilitated by a link protein, which binds to both the hyaluronan molecule and the aggrecan core protein. Each aggrecan core protein has 127 Ser-Gly sequences at which GAG chains can be added. The molecular weight of an aggrecan monomer averages 2 X 106. The entire aggregate, which may contain upward of 100 aggrecan monomers, has a molecular weight in excess of 2 X 108. [Part (a) from J. A. Buckwalter and L. Rosenberg, 1983, Coll. Rel. Res. 3:489; courtesy of L. Rosenberg.]

These aggregates give cartilage its unique gel-like properties and its resistance to deformation, essential for distributing the load in weight-bearing joints.

The aggrecan core protein (=250,000 MW) has one N-terminal globular domain that binds with high affinity to a specific decasaccharide sequence within hyaluronan. This specific sequence is generated by covalent modification of some of the repeating disaccharides in the hyaluronan chain. The interaction between aggrecan and hyaluronan is facilitated by a link protein that binds to both the aggrecan core protein and hyaluronan (Figure 6-22b). Aggrecan and the link protein have in common a "link" domain, =100 amino acids long, that is found in numerous matrix and cell-surface hyaluronan-binding proteins in both cartilaginous and noncartilaginous tissues. Almost certainly these proteins arose in the course of evolution from a single ancestral gene that encoded just this domain.

The importance of the GAG chains that are part of various matrix proteoglycans is illustrated by the rare humans who have a genetic defect in one of the enzymes required for synthesis of the GAG dermatan sulfate. These persons have many defects in their bones, joints, and muscles; do not grow to normal height; and have wrinkled skin, giving them a prematurely aged appearance. I

Fibronectins Connect Many Cells to Fibrous Collagens and Other Matrix Components

Many different cell types synthesize fibronectin, an abundant multiadhesive matrix protein found in all vertebrates. The discovery that fibronectin functions as an adhesive molecule stemmed from observations that it is present on the surfaces of normal fibroblastic cells, which adhere tightly to petri dishes in laboratory experiments, but is absent from the surfaces of tumorigenic cells, which adhere weakly. The 20 or so isoforms of fibronectin are generated by alternative splicing of the RNA transcript produced from a single gene (see Figure 4-15). Fibronectins are essential for the migration and differentiation of many cell types in embryogenesis. These proteins are also important for wound healing because they promote blood clotting and facilitate the migration of macrophages and other immune cells into the affected area.

Fibronectins help attach cells to the extracellular matrix by binding to other ECM components, particularly fibrous collagens and heparan sulfate proteoglycans, and to cell-surface adhesion receptors such as integrins (see Figure 6-2). Through their interactions with adhesion receptors (e.g., a5p1 integrin), fibronectins influence the shape and movement of cells and the organization of the cytoskeleton. Conversely, by regulating their receptor-mediated attachments to fibronectin and other ECM components, cells can sculpt the immediate ECM environment to suit their needs.

Fibronectins are dimers of two similar polypeptides linked at their C-termini by two disulfide bonds; each chain is about 60-70 nm long and 2-3 nm thick. Partial digestion

Fibrin, heparan Heparan sulfate- Collagen- Integrin- sulfate- Fibrin-

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