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▲ FIGURE 6-23 Organization of fibronectin chains. Only one of the two chains present in the dimeric fibronectin molecule is shown; both chains have very similar sequences. Each chain contains about 2446 amino acids and is composed of three types of repeating amino acid sequences. Circulating fibronectin lacks one or both of the type III repeats designated EIIIA and EIIIB owing to alternative mRNA splicing (see Figure 4-15). At least five different sequences may be present in the IIICS region as a result of alternative splicing. Each chain contains six domains (tan boxes), some of which contain specific binding sites for heparan sulfate, fibrin (a major constituent of blood clots), collagen, and cell-surface integrins. The integrin-binding domain is also known as the cell-binding domain. [Adapted from G. Paolella, M. Barone, and F. Baralle, 1993, in M. Zern and L. Reid, eds., Extracellular Matrix, Marcel Dekker, pp. 3-24.]

of fibronectin with low amounts of proteases and analysis of the fragments showed that each chain comprises six functional regions with different ligand-binding specificities (Figure 6-23). Each region, in turn, contains multiple copies of certain sequences that can be classified into one of three types. These classifications are designated fibronectin type I, II, and III repeats, on the basis of similarities in amino acid sequence, although the sequences of any two repeats of a given type are not always identical. These linked repeats give the molecule the appearance of beads on a string. The combination of different repeats composing the regions, another example of combinatorial diversity, confers on fibronectin its ability to bind multiple ligands.

One of the type III repeats in the cell-binding region of fi-bronectin mediates binding to certain integrins. The results of studies with synthetic peptides corresponding to parts of this repeat identified the tripeptide sequence Arg-Gly-Asp, usually called the RGD sequence, as the minimal sequence within this repeat required for recognition by those integrins. In one study, heptapeptides containing the RGD sequence or a variation of this sequence were tested for their ability to mediate the adhesion of rat kidney cells to a culture dish. The results showed that heptapeptides containing the RGD sequence mimicked intact fibronectin's ability to stimulate integrin-mediated adhesion, whereas variant heptapeptides lacking this sequence were ineffective (Figure 6-24).

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