Molecular Biology: Protein Structure and Functions - Stepanov V.M. 2005

Fibrillar proteins
Fibronectin

Fibronectin is a high-molecular-weight glycoprotein (molecular mass of approximately 500 kDa) composed of two nearly identical subunits. It is found in Blood serum and also occurs as insoluble aggregates in Connective Tissue. Its subunits consist of a single polypeptide chain joined at the C-terminal region by Disulfide Bonds. The polypeptide chain of each subunit sequentially folds into a series of domains corresponding to similar Regions of the polypeptide chain—essentially repeats that can be classified into three distinct types. Interestingly, analogous repeats (and consequently structurally similar domains) are found in other Proteins with different functions. For instance, type I repeats are structurally similar to one of the domains of tissue plasminogen activator.

Specific regions of the fibronectin sequence—apparently domains or groups of domains—have distinct functional roles. For example, five type I repeats spanning the amino-terminal sequence of fibronectin drive the aggregation of its molecules and participate in The formation of the Extracellular matrix by binding to heparin, a glycosaminoglycan—a massive, highly branched molecule that permeates the entire Structure OF THE extracellular matrix. The next six repeats (domains), two of which also belong to type I, are responsible for interacting with Collagen, another key extracellular matrix protein.

One of the type III repeats, located in the central region of the polypeptide chain and folded similarly to immunoglobulin domains, is formed by seven ß-structural segments. It contains a highly characteristic Arg—Gly—Asp Amino Acid Sequence (RGD in single-letter code). This sequence, which also appears in slightly different contexts in certain other proteins such as Thrombin, specifically binds to a Cell surface receptor known as integrin a₅ß₁. This interaction mediates Cell Adhesion to fibronectin and plays a vital role in the directed migration of Cells within connective tissue. Interestingly, relatively short Peptides containing the RGD sequence mimic the ability of fibronectin to interact with cell surface receptors.

Type III domains, which share structural similarities with IMMUNOGLOBULINS, are also found in other giant proteins, such as the Muscle protein titin (molecular mass 3000 kDa). Here, they are believed to give the polypeptide chain the capacity for reversible elasticity through the reversible unfolding and refolding of its compact Spatial Structure.

Further along the fibronectin molecule are domains that bind heparin, while domains near the carboxy terminus bind fibrin. A small domain located at the very C-end is responsible for the antiparallel orientation of the subunit polypeptide chains and the formation of two disulfide bonds between them.

As can be seen from the above, by combining a series of functional domains within a remarkably extended and flexible structure—domains fine-tuned for the selective binding and adhesion of macromolecules and whole cells—fibronectin provides a highly dynamic Spatial Organization of the extracellular matrix. Clearly, this function is critical for The Development of connective tissue and the Organism as a whole. Soluble fibronectin present in the blood plays a crucial Structuring role in the wound-healing process.