Interaction of Fibronectin with Fibulins

Fibulins are a family of calcium binding proteins that are found in the extracellular matrix where they play a role in development [ref]. They are modular proteins containing N-terminal complement repeats follwed by variable numbers of epidermal growth factor (EGF)-like modules (schematic). Fibulins interact with several matrix proteins and fibulin-1, which is also present in blood, associates with the D region of fibrinogen and gets incorporated into fibrin clots. In vivo fibulin-1 is found in association with elastic fibers that contain elastin and fibrillin. Of the fibulins that have been shown to interact with fibronectin, fibulin-1 is the best studied [ref1; ref2]. It seems to suppress fibronectin-mediated adhesion and motility [ref]. Fibulin-2 also bind fibronectin along with several other matrix proteins [ref]

The fibronectin binding site in fibulin-1 has been mapped to EGF-like modules 5 and 6, the same site that participates in calcium dependent self-association. Studies of the binding of fibullin-1 to microtitre wells coated with different fibronectin fragments indicate that the binding site on fibronectin resides in the hep-2 domain, probably on module III-13, the module responsible for binding of heparin. Surprisingly, heparin does not inhibit this binding suggesting that the fibulin and heparin sites are distinct. However, fluid phase 30k hep-2 fragment also fails to inhibit suggesting that the interaction between these proteins may not occur in the fluid phase. The literature on fibronectin is replete with examples of interactions that are much weaker in solution than when one component is immobilized. Examples and some possible explanations are given in the discussion of [ref]. Fibulin-2 also interacts with fibronectin and immuno-gold staining of fibroblasts in culture reveals a distinct colocalization with fibronectin at the level of resolution of the electron microscope [ref]. Interestingly, that same study showed that fibronectin does not colocalize with cross-striated fibrils of type I collagen, further evidence of lack of interaction of Fn with native collagen.