12. The extracellular matrix contains a number of non- collagen proteins that typically have multiple domains, each with specific binding sites for other matrix molecules and cell surface receptors. These proteins therefore contribute to both organizing the matrix and helping cells attach to it. The most well characterized matrix protein of this kind is fibronectin. Which one of the following characteristics is NOT TRUE for fibronectin?
    (1) It is a large glycoprotein found in all vertebrates and important for many cell-matrix interactions.
    (2) It is composed of three polypeptides that are disulfide bonded into a crosslink
    structure.
    (3) In human genome, there is only one fibronectin gene containing about 50 exons, but the transcripts can be spliced in different ways to produce many different fibronectin isoforms.
    (4) Fibronectin binds to integrin through an RGD motif. Even very short peptide containing RGD sequence can inhibit attachment of cells to fibronectin matrix.

Introduction: Fibronectin and its Essential Role

Fibronectin is a critical non-collagenous glycoprotein of the extracellular matrix (ECM) in vertebrates, contributing to tissue repair, cell adhesion, migration, and structural organization. Its modular domains contain specific binding sites for cell surface receptors and other matrix molecules, making it a multi-functional protein scaffold.​

Key Features of Fibronectin: The Truths

• Large Glycoprotein: Fibronectin is a major ECM glycoprotein found in all vertebrates, playing a vital role in cell-matrix interactions.​

• Gene and Isoforms: There is only one FN gene in humans (containing about 50 exons), but alternative splicing produces many distinct fibronectin isoforms, tailored to tissue and developmental needs.​

• RGD Motif Binding: Fibronectin binds to integrin via a specific Arg-Gly-Asp (RGD) peptide motif; even short RGD peptides can inhibit cell-fibronectin interaction by blocking integrin binding.​

The Incorrect Statement: Subunit Composition

• False claim: “It is composed of three polypeptides that are disulfide bonded into a crosslink structure.”

  • Reality: Fibronectin exists as a dimer, made of two similar subunits attached only at their C-terminal ends by disulfide bonds (not three subunits).​

  • Each subunit has multiple domains (type I, II, and III modules) responsible for different molecular interactions.​

  • This dimeric arrangement is essential for its elastic and binding properties.​

Table: Statements About Fibronectin

Fibronectin Structure Overview

• Two subunits, not three: Each chain is composed of repeated modules, providing the flexibility and multiple binding sites necessary for fibronectin’s functions.​

• Modular design: Repeats of type I, II, and III domains facilitate binding to multiple partners, such as integrins, collagen, and heparan sulfate.

• Dimerization: The C-terminal region of each subunit forms disulfide bonds, making a stable fibronectin dimer.​

Conclusion

• The statement that fibronectin contains three crosslinked polypeptides is incorrect. In reality, it is a dimer of two polypeptides, making this structural characteristic easy to confirm in modern biochemistry.​

• Recognizing this distinction is fundamental for understanding fibronectin’s multi-domain structure, alternative splicing, and central role as a matrix organizer and integrin ligand.​