Figure 19–46 Complex glycoproteins of the extracellular matrix. Many matrix glycoproteins are large scaffold proteins containing multiple copies of specific protein-interaction domains. Each domain is folded into a discrete globular structure, and many such domains are arrayed along the protein like beads on a string. this diagram shows four representative proteins among the roughly 200 matrix glycoproteins that are found in mammals. Each protein contains multiple repeat domains, with the names listed in the key at the bottom. Fibronectin, for example, contains numerous copies of three different fibronectin repeats (types I–III, labeled here as FN1, FN2, and FN3). two type III repeats near the C-terminus contain important binding sites for cell-surface integrins, whereas other FN repeats are involved in binding fibrin, collagen, and heparin, as indicated (see Figure 19–47). Other matrix proteins contain repeated sequences resembling those of epidermal growth factor (EGF), a major regulator of cell growth and proliferation; these repeats might serve a similar signaling function in matrix proteins. Other proteins contain domains, such as the insulin-like growth factor-binding protein (IGFBp) repeat, that bind and regulate the function of soluble growth factors. to add more structural diversity, many of these proteins are encoded by rNa transcripts that can be spliced in different ways, adding or removing exons, such as those in fibronectin. Finally, the scaffolding and regulatory functions of many matrix proteins are further expanded by assembly into multimeric forms, as shown at the right: fibronectin forms dimers linked at the C-termini, whereas tenascin and thrombospondin form N-terminally linked hexamers and trimers, respectively. Other domains include four repeats from thrombospondin (tSpN, tSp1, tSp3, tSp_C). VWC, von Willebrand type C; FBG, fibrinogen-like. (adapted from r.O. hynes and a. Naba, Cold Spring Harb. Perspect. Biol. 4:a004903, 2012.) as tracks along which cells can migrate or as repellents that keep cells out of forbidden areas. They can also bind and thereby influence the function of peptide growth factors and other small molecules produced by nearby cells.
The best-understood member of this class of matrix proteins is fibronectin, a large glycoprotein found in all vertebrates and important for many cell– matrix interactions. Mutant mice that are unable to make fibronectin die early in embryogenesis because their endothelial cells fail to form proper blood vessels. The defect is thought to result from abnormalities in the interactions of these cells with the surrounding extracellular matrix, which normally contains fibronectin.
Fibronectin is a dimer composed of two very large subunits joined by disulfide bonds at their C-terminal ends. Each subunit contains a series of small repeated domains, or modules, separated by short stretches of flexible polypeptide chain (Figure 19–47). Each domain is usually encoded by a separate exon, suggesting that the fibronectin gene, like the genes encoding many matrix proteins, evolved by multiple exon duplications. In the human genome, there is only one fibronectin gene, containing about 50 exons of similar size, but the transcripts can be spliced in different ways to produce multiple fibronectin isoforms (see Figure 19–46). The major repeat domain in fibronectin is called the type III fibronectin repeat, which is about 90 amino acids long and occurs at least 15 times in each subunit. This repeat is among the most common of all protein domains in vertebrates.
Fibronectin Binds to Integrins