Vitronectin

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The SMB domain (yellow) in complex with PAI-1
vitronectin
Identifiers
Symbol(s)	VTN
Entrez	7448
OMIM	193190
RefSeq	NM_000638
UniProt	P04004
Other data
Locus	Chr. 17 q11

Vitronectin is an abundant glycoprotein found in blood plasma and the extracellular matrix. Vitronectin has been speculated to be involved in hemostasis and tumor malignancy.

[edit] Structure

Vitronectin is a 75 kDa glycoprotein, consisting of 459 amino acid residues. About one third of the proteins molecular mass is composed of carbohydrates. Occasionally 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. The protein consists of three domains: The N-terminal Somatomedin B domain (1-39), a central domains with hemopexin homology (131-342) and a C-terminal domain (residues 347-459) also with hemopexin homology. Several structures has been reported for the Somatomedin B domain. Initially the protein was crystallized in complex with one of its physiological binding partners: the Plasminogen activator inhibitor-1 (PAI-1), and the structure solved for this complex^[1]. Subsequently two groups reported NMR structures of the domain^[2][3]. The Somatomedin B domain is a close knit disulfide knot, with 4 disulfide bonds within 35 residues. So far 3 different disulfide configurations have been reported for this domain^[4][5][6]. It remains to be established which one of these are correct. Homology models have been build for the central and C-terminal domains^[7].

[edit] Biology

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. Additionally 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, which serve to anchor cells to the extra cellular 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.

[edit] References

1. ↑  Zhou A, Huntington JA, Pannu NS, Carrell RW, Read RJ (2003) How vitronectin binds PAI-1 to modulate fibrinolysis and cell migration Nat Struct Biol. 2003 Jul;10(7):541-4 (full text article online: Entrez PubMed 12808446).
2. ↑  Kamikubo Y, De Guzman R, Kroon G, Curriden S, Neels JG, Churchill MJ, Dawson P, Oldziej S, Jagielska A, Scheraga HA, Loskutoff DJ, Dyson HJ. (2004) Disulfide bonding arrangements in active forms of the somatomedin B domain of human vitronectin. Biochemistry. 2004 Jun 1;43(21):6519-34 (full text article online: Entrez PubMed 15157085).
3. ↑  Mayasundari A, Whittemore NA, Serpersu EH, Peterson CB. (2004) The solution structure of the N-terminal domain of human vitronectin: proximal sites that regulate fibrinolysis and cell migration. J Biol Chem. 2004 Jul 9;279(28):29359-66. Epub 2004 Apr 30 (full text article online: Entrez PubMed 15123712).
4. ↑  Kamikubo Y, Okumura Y, Loskutoff DJ. (2002) Identification of the disulfide bonds in the recombinant somatomedin B domain of human vitronectin. J Biol Chem. 2002 Jul 26;277(30):27109-19. Epub 2002 May 17 (full text article online: Entrez PubMed 12019263).
5. ↑  Horn NA, Hurst GB, Mayasundari A, Whittemore NA, Serpersu EH, Peterson CB.(2004) Assignment of the four disulfides in the N-terminal somatomedin B domain of native vitronectin isolated from human plasma. J Biol Chem. 2004 Aug 20;279(34):35867-78. Epub 2004 Jun 1. (full text article online: Entrez PubMed 15173163).
6. ↑  Xu D, Baburaj K, Peterson CB, Xu Y (2001) Model for the three-dimensional structure of vitronectin: predictions for the multi-domain protein from threading and docking Proteins. 2001 Aug 15;44(3):312-20 (full text article online: Entrez PubMed 11455604).

Complement system - edit
Activators: C6 | C7 | C9 | MBL2 | PFC Complexes: C1Q (C1QA, C1QB, C1QG) | C3-convertase | C8 (C8A, C8B, C8G) | MAC Enzymes: BF | C1R | C1S | C2 | C3 | C4 | C5 | DF | MASP1 | MASP2 Inhibitors: C1inh | C4BP (C4BPA, C4BPB) | CLU | DAF | HF1 | IF | SERPING1 | VTN Receptors: C3AR1 | C5R1 | CR1 | CR2 | ITGAM