Fibronectin and laminin are significantly smaller than either collagens or proteoglycans, and play different roles in the extracellular matrix. Fibronectin is formed by the joining of two similar polypeptide subunits via a pair of disulfide bonds near the C-terminal of each (Figure 5). Each subunit is arranged as a linear sequence of 30 functional domains (varies slightly by species). Within each subunit, each domain acts as a semi-independent unit with respect to secondary and even tertiary structure. Structurally, there are three major types of domains (Figure 6) that can be distinguished not only by sequence, but by the binding sites they form. The Figure above shows binding sites for other fibronectins, fibrin, collagen, heparin, and syndecan. Fibronectin is therefore an excellent linkage protein between these different molecules to stabilize and strengthen the ECM.
One of the interesting aspects of fibronectin fibril formation is that the self-association site is generally hidden, but is revealed when a cell binds to the integrin-binding site. Thus cell-binding seems to nucleate the formation of fibrils, perhaps helping to form strong anchors in certain situations in which the cell is not migrating, but establishing itself permanently.
Importantly, in addition to linking a variety of extracellular matrix proteins together, fibronectin also has a site that binds to integrin receptors on cells. Whereas collagen for the most part acts as a passive substrate that cells are willing to attach to or crawl on, fibronectin can actively induce cell migration by activation of the integrins. Fibronectin expression along very specific pathways are crucial for the migration of neural crest and other cell types in development. In vitro experiments with fibroblasts and other cell types show a marked preference for areas coated with fibronectin over areas coated with collagen. This is also true in vivo: an upregulation of fibronectin in response to injury promotes migration of fibroblasts and cells associated with wound healing into the lesioned area.
The integrin binding site is characterized by the presence of an arginine-glycine-aspartic acid (RGD) sequence. If this site is abolished or mutated, the mutant bronectin does not bind to cells. Similarly, if cells are treated with high concentrations of short peptides that contain the RGD sequence, those peptides bind to the integrins, and the cells ignore fibronectin. Finally, in addition to serving as a linker between other ECM proteins, or even to cells, fibronectin can form fibrils through interaction with other fibronectins.