Vitronectin binds to integrinalpha-V beta-3 and thus promotes cell adhesion and spreading. It also inhibits the membrane-damaging effect of the terminal cytolytic complement pathway and binds to several serpins (serine protease inhibitors). It is a secreted protein and exists in either a single chain form or a clipped, two chain form held together by a disulfide bond.[6] Vitronectin has been speculated to be involved in hemostasis[8] and tumormalignancy.[9][10]
Structure
Vitronectin is a 75 kDa glycoprotein, consisting of 478 amino acidresidues. 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.
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.[11] Subsequently two groups reported NMR structures of the domain.[12][13]
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[14][15][16] but this ambiguity has been resolved by the crystal structure.[16]
The somatomedin B domain of vitronectin binds to plasminogen activator inhibitor-1 (PAI-1), and stabilizes it.[11] 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.
^Jenne D, Stanley KK (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. 26 (21): 6735–6742. doi:10.1021/bi00395a024. PMID2447940.
^Preissner KT, Seiffert D (Jan 1998). "Role of vitronectin and its receptors in haemostasis and vascular remodeling". Thrombosis Research. 89 (1): 1–21. doi:10.1016/S0049-3848(97)00298-3. PMID9610756.
^Felding-Habermann B, Cheresh DA (Oct 1993). "Vitronectin and its receptors". Current Opinion in Cell Biology. 5 (5): 864–868. doi:10.1016/0955-0674(93)90036-P. PMID7694604.
^Kamikubo Y, De Guzman R, Kroon G, Curriden S, Neels JG, Churchill MJ, et al. (Jun 2004). "Disulfide bonding arrangements in active forms of the somatomedin B domain of human vitronectin". Biochemistry. 43 (21): 6519–6534. doi:10.1021/bi049647c. PMID15157085.
^ abcXu D, Baburaj K, Peterson CB, Xu Y (Aug 2001). "Model for the three-dimensional structure of vitronectin: predictions for the multi-domain protein from threading and docking". Proteins. 44 (3): 312–320. doi:10.1002/prot.1096. PMID11455604. S2CID24765480.
