Vitronectin

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Vitronectin

The SMB domain (yellow) in complex with PAI-1
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols VTN ; V75; VN; VNT
External IDs OMIM193190 MGI98940 HomoloGene532 ChEMBL: 1075314 GeneCards: VTN Gene
RNA expression pattern
PBB GE VTN 204534 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 7448 22370
Ensembl ENSG00000255604 ENSMUSG00000017344
UniProt P04004 P29788
RefSeq (mRNA) NM_000638 NM_011707
RefSeq (protein) NP_000629 NP_035837
Location (UCSC) Chr 17:
26.69 – 26.7 Mb
Chr 11:
78.5 – 78.5 Mb
PubMed search [1] [2]

Vitronectin also known as VTN is a protein that in humans is encoded by the VTN gene.[1][2]

The protein encoded by this gene is a member of the pexin family. Vitronectin is an abundant glycoprotein found in serum and the extracellular matrix and promotes cell adhesion and spreading, 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.[1] Vitronectin has been speculated to be involved in hemostasis[3] and tumor malignancy.[4]

Structure[edit]

Vitronectin is a 75 kDa glycoprotein, consisting of 459 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:

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.[5] Subsequently two groups reported NMR structures of the domain.[6][7]

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[8][9][10] but this ambiguity has been resolved by the crystal structure.[10]

Homology models have been built for the central and C-terminal domains.[10]

Function[edit]

The somatomedin B domain of vitronectin binds to plasminogen activator inhibitor-1 (PAI-1), and stabilizes it.[5] 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[edit]

  1. ^ a b "Entrez Gene: M Vitronectin". 
  2. ^ Jenne D, Stanley KK (October 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): 6735–42. doi:10.1021/bi00395a024. PMID 2447940. 
  3. ^ Preissner KT, Seiffert D (January 1998). "Role of vitronectin and its receptors in haemostasis and vascular remodeling" (– Scholar search). Thromb. Res. 89 (1): 1–21. doi:10.1016/S0049-3848(97)00298-3. PMID 9610756. [dead link]
  4. ^ Felding-Habermann B, Cheresh DA (October 1993). "Vitronectin and its receptors". Curr. Opin. Cell Biol. 5 (5): 864–8. doi:10.1016/0955-0674(93)90036-P. PMID 7694604. 
  5. ^ a b Zhou A, Huntington JA, Pannu NS, Carrell RW, Read RJ (July 2003). "How vitronectin binds PAI-1 to modulate fibrinolysis and cell migration". Nat. Struct. Biol. 10 (7): 541–4. doi:10.1038/nsb943. PMID 12808446. 
  6. ^ Kamikubo Y, De Guzman R, Kroon G, Curriden S, Neels JG, Churchill MJ, Dawson P, Ołdziej S, Jagielska A, Scheraga HA, Loskutoff DJ, Dyson HJ (June 2004). "Disulfide bonding arrangements in active forms of the somatomedin B domain of human vitronectin". Biochemistry 43 (21): 6519–34. doi:10.1021/bi049647c. PMID 15157085. 
  7. ^ Mayasundari A, Whittemore NA, Serpersu EH, Peterson CB (July 2004). "The solution structure of the N-terminal domain of human vitronectin: proximal sites that regulate fibrinolysis and cell migration". J. Biol. Chem. 279 (28): 29359–66. doi:10.1074/jbc.M401279200. PMID 15123712. 
  8. ^ Kamikubo Y, Okumura Y, Loskutoff DJ (July 2002). "Identification of the disulfide bonds in the recombinant somatomedin B domain of human vitronectin". J. Biol. Chem. 277 (30): 27109–19. doi:10.1074/jbc.M200354200. PMID 12019263. 
  9. ^ Horn NA, Hurst GB, Mayasundari A, Whittemore NA, Serpersu EH, Peterson CB (August 2004). "Assignment of the four disulfides in the N-terminal somatomedin B domain of native vitronectin isolated from human plasma". J. Biol. Chem. 279 (34): 35867–78. doi:10.1074/jbc.M405716200. PMID 15173163. 
  10. ^ a b c Xu D, Baburaj K, Peterson CB, Xu Y (August 2001). "Model for the three-dimensional structure of vitronectin: predictions for the multi-domain protein from threading and docking". Proteins 44 (3): 312–20. doi:10.1002/prot.1096. PMID 11455604. 

External links[edit]