ADAM metallopeptidase with thrombospondin type 1 motif, 13
|| ADAMTS13; TTP; C9orf8; DKFZp434C2322; FLJ42993; MGC118899; MGC118900; VWFCP; vWF-CP
| External IDs
|| OMIM: 604134 MGI: 2685556 Homologene: 16372
| Molecular Function:
|| • metalloendopeptidase activity|
• integrin binding
• calcium ion binding
• protein binding
• peptidase activity
• zinc ion binding
| Cellular Component:
|| • proteinaceous extracellular matrix|
• extracellular space
• cell surface
| Biological Process:
|| • proteolysis|
• cell-matrix adhesion
• integrin-mediated signaling pathway
• glycoprotein metabolic process
• protein processing
• platelet activation
• peptide catabolic process
| RNA expression pattern
More reference expression data
|| NM_139028 (mRNA)|
|| Chr 9: 135.28 - 135.31 Mb
| Pubmed search
ADAMTS13 (A Disintegrin And Metalloproteinase with a ThromboSpondin type 1 motif, member 13) is a zinc-containing metalloprotease enzyme that cleaves von Willebrand factor (vWf), a large protein involved in blood clotting. It is also known as von Willebrand factor-cleaving protease (VWFCP). It is secreted in blood and degrades large vWf multimers, decreasing their activity.
Additional recommended knowledge
The ADAMTS13 gene maps to the ninth chromosome (9q34).
Discovery and function
Since 1982 it had been known that thrombotic thrombocytopenic purpura (TTP), one of the microangiopathic hemolytic anemias (see below), was characterised in its familial form by the presence in plasma of unusually large von Willebrand factor multimers (ULVWF).
In 1994, VWF was shown to be cleaved between a tyrosine at position 1605 and a methionine at 1606 by a plasma metalloprotease when it was exposed to high levels of shear stress. In 1996, two research groups independently further characterized the enzyme that cleaved VWF. In the next two years, the same two groups showed that the congenital deficiency of vWf-cleaving protease was associated with formation of platelet microthrombi in the small blood vessels. In addition, they reported that in majority of patients IgG antibodies, directed against this enzyme, caused TTP in non-familial cases.
Genomically, ADAMTS13 shares many properties with the 19 member ADAMTS family, all of which are characterised by a protease domain (the part that performs the protein hydrolysis), an adjacent disintegrin domain and one or more thrombospondin domains. ADAMTS13 in fact has eight thrombospondin domains. It has no hydrophobic transmembrane domain, and hence it not anchored in the cell membrane.
Role in disease
Deficiency of ADAMTS13 was originally discovered in Upshaw-Shulman syndrome, the recurring familial form of TTP. By that time it was already suspected that TTP occurred in the autoimmune form as well, owing to its response to plasmapheresis and characterisation of IgG inhibitors. Since the discovery of ADAMTS13, specific epitopes on its surface have been shown to be the target of inhibitory antibodies.
Especially since the link between aortic valve stenosis and angiodysplasia was proven to be due to high shear stress (Heyde's syndrome), it has been accepted that increased exposure of vWf to ADAMTS13 due to various reasons would predispose to bleeding by causing increased degradation of vWf. This phenomenon is characterised by a form of von Willebrand disease (type 2a).
- ^ a b c d e f g Levy GG, Motto DG, Ginsburg D (2005). "ADAMTS13 turns 3". Blood 106 (1): 11–7. doi:10.1182/blood-2004-10-4097. PMID 15774620.
- ^ Tsai HM (2003). "Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura". J. Am. Soc. Nephrol. 14 (4): 1072–81. PMID 12660343.
- ^ Furlan M, Lämmle B (2001). "Aetiology and pathogenesis of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome: the role of von Willebrand factor-cleaving protease". Best Pract Res Clin Haematol 14 (2): 437–54. doi:10.1053/beha.2001.0142. PMID 11686108.
- Furlan M, Lammle B. Aetiology and pathogenesis of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome: the role of von Willebrand factor-cleaving protease. Best Pract Res Clin Haematol 2001;14:437-54. PMID 11686108.
- Tsai HM. Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura. J Am Soc Nephrol 2003;14:1072-81. PMID 12660343.
- Tang BL (2001). "ADAMTS: a novel family of extracellular matrix proteases.". Int. J. Biochem. Cell Biol. 33 (1): 33-44. PMID 11167130.
- Fujimura Y, Matsumoto M, Yagi H, et al. (2002). "Von Willebrand factor-cleaving protease and Upshaw-Schulman syndrome.". Int. J. Hematol. 75 (1): 25-34. PMID 11843286.
- Zheng X, Majerus EM, Sadler JE (2003). "ADAMTS13 and TTP.". Curr. Opin. Hematol. 9 (5): 389-94. PMID 12172456.
- Tsai HM (2003). "Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura.". J. Mol. Med. 80 (10): 639-47. doi:10.1007/s00109-002-0369-8. PMID 12395148.
- Tsai HM (2003). "Platelet activation and the formation of the platelet plug: deficiency of ADAMTS13 causes thrombotic thrombocytopenic purpura.". Arterioscler. Thromb. Vasc. Biol. 23 (3): 388-96. doi:10.1161/01.ATV.0000058401.34021.D4. PMID 12615692.
- Tsai HM (2003). "Is severe deficiency of ADAMTS-13 specific for thrombotic thrombocytopenic purpura? Yes.". J. Thromb. Haemost. 1 (4): 625-31. PMID 12871390.
- Remuzzi G (2003). "Is ADAMTS-13 deficiency specific for thrombotic thrombocytopenic purpura? No.". J. Thromb. Haemost. 1 (4): 632-4. PMID 12871391.
- Moake JL (2004). "von Willebrand factor, ADAMTS-13, and thrombotic thrombocytopenic purpura.". Semin. Hematol. 41 (1): 4-14. PMID 14727254.
- López JA, Dong JF (2004). "Cleavage of von Willebrand factor by ADAMTS-13 on endothelial cells.". Semin. Hematol. 41 (1): 15-23. PMID 14727255.
- Plaimauer B, Scheiflinger F (2004). "Expression and characterization of recombinant human ADAMTS-13.". Semin. Hematol. 41 (1): 24-33. PMID 14727256.
- Kokame K, Miyata T (2004). "Genetic defects leading to hereditary thrombotic thrombocytopenic purpura.". Semin. Hematol. 41 (1): 34-40. PMID 14727257.
- Schneppenheim R, Budde U, Hassenpflug W, Obser T (2004). "Severe ADAMTS-13 deficiency in childhood.". Semin. Hematol. 41 (1): 83-9. PMID 14727263.
- Kremer Hovinga JA, Studt JD, Lämmle B (2005). "The von Willebrand factor-cleaving protease (ADAMTS-13) and the diagnosis of thrombotic thrombocytopenic purpura (TTP).". Pathophysiol. Haemost. Thromb. 33 (5-6): 417-21. doi:10.1159/000083839. PMID 15692254.
- Levy GG, Motto DG, Ginsburg D (2005). "ADAMTS13 turns 3.". Blood 106 (1): 11-7. doi:10.1182/blood-2004-10-4097. PMID 15774620.
- George JN (2005). "ADAMTS13, thrombotic thrombocytopenic purpura, and hemolytic uremic syndrome.". Curr. Hematol. Rep. 4 (3): 167-9. PMID 15865866.
- Dong JF (2005). "Cleavage of ultra-large von Willebrand factor by ADAMTS-13 under flow conditions.". J. Thromb. Haemost. 3 (8): 1710-6. doi:10.1111/j.1538-7836.2005.01360.x. PMID 16102037.