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Vitronectin Background
Vitronectin (VTN) is synthesized as a precursor polypeptide consisting of 478 amino acids (aa). The precursor protein sequence consists of a 19 aa signal peptide and 459 aa mature protein.
Table 1 The physicochemical properties of the mature protein
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pI
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4.75-5.25
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Mr (K) Predicted
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52.5
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Mr (K) Observed
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~75
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N-linked glycosylation sites
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3 (86, 169, 242)
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Phosphorylation sites
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3 (Thr-50, Thr-57, Ser-263)
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Sulphation sites
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2 (Tyr-56, Tyr-59)
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Vitronectin Structure
The first 43 aa on the VTN molecule is identical to the somatomedin-B (SMB) consensus sequence. This is followed by a triplet residue Arg-Gly-Asp (RGD) (aa residues 45-47) that functions as an anchoring site for cell integrin receptors. Downstream of the RGD sequence is a stretch of highly acidic amino acids (residues 53-64) that has binding affinity for the thrombin-antithrombin III complex (TAT) and collagen. VTN has three heparin-binding sites, namely HBD-1, HBD-2 and HBD-3 that are located at residues 82-137, 175-219, and 346-361, respectively. VTN harbours four hemopexin repeats (Hpx; heme-binding protein in plasma) distributed along the central region (Hpx-1, Hpx-2, and Hpx-3 at residues 142-285) and C-terminal edge (Hpx-4 at residues 406-453). As a complement regulator, more than half of the VTN molecule (residues 51-310) accommodates interaction sites for complement proteins C5b-C7 and C9.
Fig. 1 Domain arrangement of vitronectin.1
VTN circulates in two forms in human blood: (1) a 75 kDa-full length single-chain fragment and (2) a disulfide-linked dimer consisting of a two-chain fragment (65 and 10 kDa). The two-chain fragment is a product of the 75-kDa mature protein cleaved by an unknown protease between Arg-379 and Ala-380. The proteolytic products are linked by a single disulfide bridge at residues Cys-274 and Cys-453 of N-terminal of 65 kDa and C-terminal 10 kDa fragments, respectively. In addition, VTN has a high degree of conformational flexible structure. In circulating blood, VTN exists as a heterogeneous mixture consisting of different forms that serve different biological roles, either as monomeric or multimeric VTN.
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Vitronectin Function
Key biological functions of VTN, mainly in its activated form, include (1) regulation of the innate immune system, (2) maintenance of vascular haemostasis (thrombosis and fibrinolysis), and, finally, (3) promotion of cell adhesion and migration in tissue repair and regeneration. To protect host cells from innocent bystander cell lysis (self-killing), VTN functions as a regulator at the terminal lytic step of the (1) complement pathway and (2) perforin-mediated cell lysis. In the terminal complement pathway, VTN interacts with the premembrane attack complex (pre-MAC) of C5b-7 that in turn occupies the metastable membrane binding site of the complex. This eventually hinders the insertion of the C5b-7 into the cell membrane and thus precludes the downstream completion with C9 to form the MAC lytic pore (C5b-9). Another regulatory mechanism is via interaction of free (nonmembrane inserted) C5b-7, C5b-8 and C5b-9 complex with VTN into water-soluble complexes (sC5b-7, etc.) that are haemolytically nonactive.
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Vitronectin Tissue Distribution
VTN is mainly synthesized in the liver as a single-chain 75 kDa polypeptide precursor and is released to the circulation and interstitial space or ECM through receptor-mediated trans-, endo- or exocytosis. In addition to the liver as the major organ of VTN biosynthesis, appreciable amounts of VTN deposits or/and its mRNA are also detected in various normal tissues and organs. VTN is present in normal human plasma at a concentration between 200 and 400 μg/mL (constitutes 0.2%-0.5% of total plasma proteins), mainly as a monomeric form and is predominantly derived from the liver. VTN deposited within platelet (mainly as multimeric aggregates) is the second main circulating pool of VTN and accounts for 0.8%-1% of the total circulating VTN. Tissues experiencing stress or trauma had upregulated levels of VTN mRNA as a proinflammatory response with increased VTN accumulated in the extravascular space of the traumatized tissues.
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Reference
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Gibson, Angelia D., et al. "Orientation of heparin-binding sites in native vitronectin: analyses of ligand binding to the primary glycosaminoglycan-binding site indicate that putative secondary sites are not functional." Journal of Biological Chemistry 274.10 (1999): 6432-6442.
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