Vitronectin

Structure

Vitronectin is a 75 kDa glycoprotein, consisting of 478 amino acid residues. About one-third of the protein's molecular mass is composed of carbohydrates. On occasion, the protein is cleaved after arginine 379, to produce two-chain vitronectin, where the two parts are linked by a disulfide bond. No high-resolution structure has been determined experimentally yet, except for the N-terminal domain.

The protein consists of three domains:

• The N-terminal Somatomedin B domain (1-39)
• A central domains with hemopexin homology (131-342)
• A C-terminal domain (residues 347-459) also with hemopexin homology.

Several structures has been reported for the Somatomedin B domain. The protein was initially crystallized in complex with one of its physiological binding partners: the Plasminogen activator inhibitor-1 (PAI-1) and the structure solved for this complex. Subsequently two groups reported NMR structures of the domain.

The somatomedin B domain is a close-knit disulfide knot, with 4 disulfide bonds within 35 residues. Different disulfide configurations had been reported for this domain but this ambiguity has been resolved by the crystal structure.

Homology models have been built for the central and C-terminal domains.

Function

The somatomedin B domain of vitronectin binds to plasminogen activator inhibitor-1 (PAI-1), and stabilizes it. Thus vitronectin serves to regulate proteolysis initiated by plasminogen activation. In addition, vitronectin is a component of platelets and is, thus, involved in hemostasis. Vitronectin contains an RGD (45-47) sequence, which is a binding site for membrane-bound integrins, e.g., the vitronectin receptor, which serve to anchor cells to the extracellular matrix. The Somatomedin B domain interacts with the urokinase receptor, and this interaction has been implicated in cell migration and signal transduction. High plasma levels of both PAI-1 and the urokinase receptor have been shown to correlate with a negative prognosis for cancer patients. Cell adhesion and migration are directly involved in cancer metastasis, which provides a probable mechanistic explanation for this observation.

References

References

1. Boron, Walter F. and Boulpaep, Emile L. "Medical Physiology". Saunders, 2012, p.1097.
2. "Entrez Gene: M Vitronectin".
3. (Oct 1987). "Nucleotide sequence and organization of the human S-protein gene: repeating peptide motifs in the "pexin" family and a model for their evolution". Biochemistry.
4. (Jan 1998). "Role of vitronectin and its receptors in haemostasis and vascular remodeling". Thrombosis Research.
5. (Oct 1993). "Vitronectin and its receptors". Current Opinion in Cell Biology.
6. (2009). "Identification of Vitronectin as an Extrinsic Inducer of Cancer Stem Cell Differentiation and Tumor Formation". Stem Cells.
7. (Jul 2003). "How vitronectin binds PAI-1 to modulate fibrinolysis and cell migration". Nature Structural Biology.
8. (Jun 2004). "Disulfide bonding arrangements in active forms of the somatomedin B domain of human vitronectin". Biochemistry.
9. (Jul 2004). "The solution structure of the N-terminal domain of human vitronectin: proximal sites that regulate fibrinolysis and cell migration". The Journal of Biological Chemistry.
10. (Jul 2002). "Identification of the disulfide bonds in the recombinant somatomedin B domain of human vitronectin". The Journal of Biological Chemistry.
11. (Aug 2004). "Assignment of the four disulfides in the N-terminal somatomedin B domain of native vitronectin isolated from human plasma". The Journal of Biological Chemistry.
12. (Aug 2001). "Model for the three-dimensional structure of vitronectin: predictions for the multi-domain protein from threading and docking". Proteins.