ADAMTS13

ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13)—also known as von Willebrand factor-cleaving protease (VWFCP)—is a zinc-containing metalloprotease enzyme that cleaves von Willebrand factor (vWf), a large protein involved in blood clotting. It is secreted into the blood and degrades large vWf multimers, decreasing their activity, hence ADAMTS13 acts to reduce thrombus formation.

ADAMTS13
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3GHM, 3GHN
Identifiers
Aliases	ADAMTS13, ADAM-TS13, ADAMTS-13, C9orf8, VWFCP, vWF-CP, ADAM metallopeptidase with thrombospondin type 1 motif 13
External IDs	OMIM: 604134; MGI: 2685556; HomoloGene: 16372; GeneCards: ADAMTS13; OMA:ADAMTS13 - orthologs
Gene location (Human) Chr. Chromosome 9 (human) Band 9q34.2 Start 133,414,358 bp End 133,459,402 bp
Gene location (Mouse) Chr. Chromosome 2 (mouse) Band 2|2 A3 Start 26,863,428 bp End 26,899,640 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right lobe of liver right hemisphere of cerebellum right uterine tube right frontal lobe right testis left testis primary visual cortex pituitary gland apex of heart Brodmann area 9 Top expressed in liver dentate gyrus of hippocampal formation granule cell morula bone marrow embryo esophagus hippocampus proper primary visual cortex yolk sac superior frontal gyrus More reference expression data BioGPS More reference expression data
Gene ontology Molecular function calcium ion binding endopeptidase activity metal ion binding integrin binding peptidase activity protein binding metalloendopeptidase activity hydrolase activity metallopeptidase activity zinc ion binding Cellular component endoplasmic reticulum lumen extracellular region cell surface extracellular space extracellular matrix Biological process hemostasis glycoprotein metabolic process response to interleukin-4 response to interferon-gamma protein processing blood coagulation proteolysis platelet activation response to tumor necrosis factor integrin-mediated signaling pathway cell-matrix adhesion response to toxic substance peptide catabolic process response to potassium ion cellular response to interferon-gamma cellular response to lipopolysaccharide response to amine cellular response to interleukin-4 cellular response to tumor necrosis factor Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 11093 279028 Ensembl ENSG00000160323 ENSG00000281244 ENSMUSG00000014852 UniProt Q76LX8 Q769J6 RefSeq (mRNA) NM_139025 NM_139026 NM_139027 NM_139028 NM_001001322 NM_001290463 NM_001290464 NM_001290465 RefSeq (protein) NP_620594 NP_620595 NP_620596 NP_001001322 NP_001277392 NP_001277393 NP_001277394 Location (UCSC) Chr 9: 133.41 – 133.46 Mb Chr 2: 26.86 – 26.9 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

Genetics

The ADAMTS13 gene maps to the ninth chromosome (9q34).

Discovery

Since 1982 it had been known that thrombotic thrombocytopenic purpura (TTP), one of the microangiopathic hemolytic anemias (see below), was characterized 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 enzyme when it was exposed to high levels of shear stress. In 1996, two research groups independently further characterized this enzyme. In the next two years, the same two groups showed that the congenital deficiency of a vWF-cleaving protease was associated with formation of platelet microthrombi in the small blood vessels. In addition, they reported that IgG antibodies directed against this same enzyme caused TTP in a majority of non-familial cases.

Proteomics

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 is not anchored in the cell membrane.

Role in disease

Deficiency of ADAMTS13 was originally discovered in Upshaw Schulman Syndrome, the recurring familial form of thrombotic thrombocytopenic purpura. 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.

Low levels of ADAMTS13 are also associated with an increased risk of arterial thrombosis, including myocardial infarction and cerebrovascular disease.

Finally, 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).

See also

• ADAMTS5

Further reading

• Tang BL (January 2001). "ADAMTS: a novel family of extracellular matrix proteases". The International Journal of Biochemistry & Cell Biology. 33 (1): 33–44. doi:10.1016/S1357-2725(00)00061-3. PMID 11167130.
• Fujimura Y, Matsumoto M, Yagi H, Yoshioka A, Matsui T, Titani K (January 2002). "Von Willebrand factor-cleaving protease and Upshaw-Schulman syndrome". International Journal of Hematology. 75 (1): 25–34. doi:10.1007/BF02981975. PMID 11843286. S2CID 19926816.
• Zheng X, Majerus EM, Sadler JE (September 2002). "ADAMTS13 and TTP". Current Opinion in Hematology. 9 (5): 389–94. doi:10.1097/00062752-200209000-00001. PMID 12172456. S2CID 19457473.
• Tsai HM (October 2002). "Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura". Journal of Molecular Medicine. 80 (10): 639–47. doi:10.1007/s00109-002-0369-8. PMID 12395148. S2CID 24992893.
• Tsai HM (March 2003). "Platelet activation and the formation of the platelet plug: deficiency of ADAMTS13 causes thrombotic thrombocytopenic purpura". Arteriosclerosis, Thrombosis, and Vascular Biology. 23 (3): 388–96. doi:10.1161/01.ATV.0000058401.34021.D4. PMID 12615692.
• Tsai HM (April 2003). "Is severe deficiency of ADAMTS-13 specific for thrombotic thrombocytopenic purpura? Yes". Journal of Thrombosis and Haemostasis. 1 (4): 625–31. doi:10.1046/j.1538-7836.2003.00169.x. PMID 12871390. S2CID 26485194.
• Remuzzi G (April 2003). "Is ADAMTS-13 deficiency specific for thrombotic thrombocytopenic purpura? No". Journal of Thrombosis and Haemostasis. 1 (4): 632–4. doi:10.1046/j.1538-7836.2003.00170.x. PMID 12871391. S2CID 10742104.
• Moake JL (January 2004). "von Willebrand factor, ADAMTS-13, and thrombotic thrombocytopenic purpura". Seminars in Hematology. 41 (1): 4–14. doi:10.1053/j.seminhematol.2003.10.003. PMID 14727254.
• López JA, Dong JF (January 2004). "Cleavage of von Willebrand factor by ADAMTS-13 on endothelial cells". Seminars in Hematology. 41 (1): 15–23. doi:10.1053/j.seminhematol.2003.10.004. PMID 14727255.
• Plaimauer B, Scheiflinger F (January 2004). "Expression and characterization of recombinant human ADAMTS-13". Seminars in Hematology. 41 (1): 24–33. doi:10.1053/j.seminhematol.2003.10.006. PMID 14727256.
• Kokame K, Miyata T (January 2004). "Genetic defects leading to hereditary thrombotic thrombocytopenic purpura". Seminars in Hematology. 41 (1): 34–40. doi:10.1053/j.seminhematol.2003.10.002. PMID 14727257.
• Schneppenheim R, Budde U, Hassenpflug W, Obser T (January 2004). "Severe ADAMTS-13 deficiency in childhood". Seminars in Hematology. 41 (1): 83–9. doi:10.1053/j.seminhematol.2003.10.007. 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)". Pathophysiology of Haemostasis and Thrombosis. 33 (5–6): 417–21. doi:10.1159/000083839. PMID 15692254.
• Levy GG, Motto DG, Ginsburg D (July 2005). "ADAMTS13 turns 3". Blood. 106 (1): 11–7. doi:10.1182/blood-2004-10-4097. PMID 15774620. S2CID 25645477.
• George JN (May 2005). "ADAMTS13, thrombotic thrombocytopenic purpura, and hemolytic uremic syndrome". Current Hematology Reports. 4 (3): 167–9. PMID 15865866.
• Dong JF (August 2005). "Cleavage of ultra-large von Willebrand factor by ADAMTS-13 under flow conditions". Journal of Thrombosis and Haemostasis. 3 (8): 1710–6. doi:10.1111/j.1538-7836.2005.01360.x. PMID 16102037. S2CID 33464866.
• Matsukawa M, Kaikita K, Soejima K, Fuchigami S, Nakamura Y, Honda T, Tsujita K, Nagayoshi Y, Kojima S, Shimomura H, Sugiyama S, Fujimoto K, Yoshimura M, Nakagaki T, Ogawa H (September 2007). "Serial changes in von Willebrand factor-cleaving protease (ADAMTS13) and prognosis after acute myocardial infarction". The American Journal of Cardiology. 100 (5): 758–63. doi:10.1016/j.amjcard.2007.03.095. PMID 17719316.

External links

• The MEROPS online database for peptidases and their inhibitors: M12.241
• Online Mendelian Inheritance in Man (OMIM): 274150
• Secreted protein database entry
• Human ADAMTS13 genome location and ADAMTS13 gene details page in the UCSC Genome Browser.
• Overview of all the structural information available in the PDB for UniProt: Q76LX8 (A disintegrin and metalloproteinase with thrombospondin motifs 13) at the PDBe-KB.