ADAMTS4

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Identifiers
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External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
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A disintegrin and metalloproteinase with thrombospondin motifs 4 is an enzyme that in humans is encoded by the ADAMTS4 gene.[1]

This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family. Members of the family share several distinct protein modules, including a propeptide region, a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. Individual members of this family differ in the number of C-terminal TS motifs, and some have unique C-terminal domains. The enzyme encoded by this gene lacks a C-terminal TS motif. It can degrade aggrecan, a major proteoglycan of cartilage, brevican, a brain-specific extracellular matrix protein, neurocan and versican. The cleavage of aggrecan and brevican suggests key roles of this enzyme in arthritic disease and in the central nervous system, potentially, in the progression of glioma.[2]

Structure

ADAMTS4 is the shortest known ADAMTS, lacking the C-terminal domain and is the only non-glycosylated ADAMTS.[3] It also only has one thrombospondin type 1 motif (TSR), whereas all the other ADAMTS have two or more TSRs. The TSR is important for binding of the enzyme to the extracellular matrix and hence its substrate specificity. Adjacent to the C-terminal TSR is a disintegrin-like domain, a cysteine-rich region that stacks against the active-site of the enzyme when in its final folded tertiary structure.[4]

Function

ADAMTS4 is capable of cleaving all the large chondroitin sulfate hyaluronan-binding proteoglycans (CSPGs), including aggrecan, brevican, neurocan and versican. Like ADAMTS5, it can be effectively inhibited by tissue inhibitor of metalloproteinase-3 (TIMP3)[5] and this inhibition can be enhanced in the presence of aggrecan.[6] In addition to TIMP3, it can also be inhibited by calcium pentosan polysulfate.[7]

ADAMTS4 is expressed in ovary, spinal cord, adrenal cortex, ciliary ganglion, trigeminal ganglion, brain, retina, pancreas (islets), fetal lung, breast myoepithelial cells, tendon and cartilage.[3]

Clinical Significance

ADAMTS4 (and ADAMTS5) are the major proteinases responsible for the degradation of proteoglycans in articular cartilage in osteoarthritis.[8] Which of these aggrecanases is more important in cartilage degradation appears to be species-specific, with ADAMTS4 more important in human disease (but ADAMTS5 more important in mouse models of osteoarthritis).

Alternative names

  • Aggrecanase-1 (initial name reflecting its ability to cleave aggrecan)

References

  1. ↑ Tang BL, Hong W (Feb 1999). "ADAMTS: a novel family of proteases with an ADAM protease domain and thrombospondin 1 repeats". FEBS Letters. 445 (2–3): 223–5. doi:10.1016/S0014-5793(99)00119-2. PMID 10094461.
  2. ↑ "Entrez Gene: ADAMTS4 ADAM metallopeptidase with thrombospondin type 1 motif, 4".
  3. ↑ 3.0 3.1 Kelwick R, Desanlis I, Wheeler GN, Edwards DR (2015). "The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) family". Genome Biol. 16 (1): 113. doi:10.1186/s13059-015-0676-3. PMC 4448532. PMID 26025392.
  4. ↑ Mosyak L, Georgiadis K, Shane T, Svenson K, Hebert T, McDonagh T, Mackie S, Olland S, Lin L, Zhong X, Kriz R, Reifenberg EL, Collins-Racie LA, Corcoran C, Freeman B, Zollner R, Marvell T, Vera M, Sum PE, Lavallie ER, Stahl M, Somers W (2008). "Crystal structures of the two major aggrecan degrading enzymes, ADAMTS4 and ADAMTS5". Protein Sci. 17 (1): 16–21. doi:10.1110/ps.073287008. PMC 2144589. PMID 18042673.
  5. ↑ Troeberg L, Fushimi K, Scilabra SD, Nakamura H, Dive V, Thøgersen IB, Enghild JJ, Nagase H (2009). "The C-terminal domains of ADAMTS-4 and ADAMTS-5 promote association with N-TIMP-3". Matrix Biol. 28 (8): 463–9. doi:10.1016/j.matbio.2009.07.005. PMC 2835468. PMID 19643179.
  6. ↑ Wayne GJ, Deng SJ, Amour A, Borman S, Matico R, Carter HL, Murphy G (2007). "TIMP-3 inhibition of ADAMTS-4 (Aggrecanase-1) is modulated by interactions between aggrecan and the C-terminal domain of ADAMTS-4". J. Biol. Chem. 282 (29): 20991–8. doi:10.1074/jbc.M610721200. PMID 17470431.
  7. ↑ Takizawa M, Yatabe T, Okada A, Chijiiwa M, Mochizuki S, Ghosh P, Okada Y (2008). "Calcium pentosan polysulfate directly inhibits enzymatic activity of ADAMTS4 (aggrecanase-1) in osteoarthritic chondrocytes". FEBS Lett. 582 (19): 2945–9. doi:10.1016/j.febslet.2008.07.036. PMID 18671975.
  8. ↑ Bondeson J, Wainwright S, Hughes C, Caterson B (2008). "The regulation of the ADAMTS4 and ADAMTS5 aggrecanases in osteoarthritis: a review". Clin. Exp. Rheumatol. 26 (1): 139–45. PMID 18328163.

Further reading

  • Tang BL (Jan 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.
  • Hirohata S (Nov 2001). "[ADAMTS family--new extracellular matrix degrading enzyme]". Seikagaku. The Journal of Japanese Biochemical Society. 73 (11): 1333–7. PMID 11831030.
  • Ishikawa K, Nagase T, Suyama M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O (Jun 1998). "Prediction of the coding sequences of unidentified human genes. X. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro". DNA Research. 5 (3): 169–76. doi:10.1093/dnares/5.3.169. PMID 9734811.
  • Tortorella MD, Burn TC, Pratta MA, Abbaszade I, Hollis JM, Liu R, Rosenfeld SA, Copeland RA, Decicco CP, Wynn R, Rockwell A, Yang F, Duke JL, Solomon K, George H, Bruckner R, Nagase H, Itoh Y, Ellis DM, Ross H, Wiswall BH, Murphy K, Hillman MC, Hollis GF, Newton RC, Magolda RL, Trzaskos JM, Arner EC (Jun 1999). "Purification and cloning of aggrecanase-1: a member of the ADAMTS family of proteins". Science. 284 (5420): 1664–6. doi:10.1126/science.284.5420.1664. PMID 10356395.
  • Abbaszade I, Liu RQ, Yang F, Rosenfeld SA, Ross OH, Link JR, Ellis DM, Tortorella MD, Pratta MA, Hollis JM, Wynn R, Duke JL, George HJ, Hillman MC, Murphy K, Wiswall BH, Copeland RA, Decicco CP, Bruckner R, Nagase H, Itoh Y, Newton RC, Magolda RL, Trzaskos JM, Burn TC (Aug 1999). "Cloning and characterization of ADAMTS11, an aggrecanase from the ADAMTS family". The Journal of Biological Chemistry. 274 (33): 23443–50. doi:10.1074/jbc.274.33.23443. PMID 10438522.
  • Hurskainen TL, Hirohata S, Seldin MF, Apte SS (Sep 1999). "ADAM-TS5, ADAM-TS6, and ADAM-TS7, novel members of a new family of zinc metalloproteases. General features and genomic distribution of the ADAM-TS family". The Journal of Biological Chemistry. 274 (36): 25555–63. doi:10.1074/jbc.274.36.25555. PMID 10464288.
  • Tortorella MD, Pratta M, Liu RQ, Austin J, Ross OH, Abbaszade I, Burn T, Arner E (Jun 2000). "Sites of aggrecan cleavage by recombinant human aggrecanase-1 (ADAMTS-4)". The Journal of Biological Chemistry. 275 (24): 18566–73. doi:10.1074/jbc.M909383199. PMID 10751421.
  • Matthews RT, Gary SC, Zerillo C, Pratta M, Solomon K, Arner EC, Hockfield S (Jul 2000). "Brain-enriched hyaluronan binding (BEHAB)/brevican cleavage in a glioma cell line is mediated by a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family member". The Journal of Biological Chemistry. 275 (30): 22695–703. doi:10.1074/jbc.M909764199. PMID 10801887.
  • Tortorella M, Pratta M, Liu RQ, Abbaszade I, Ross H, Burn T, Arner E (Aug 2000). "The thrombospondin motif of aggrecanase-1 (ADAMTS-4) is critical for aggrecan substrate recognition and cleavage". The Journal of Biological Chemistry. 275 (33): 25791–7. doi:10.1074/jbc.M001065200. PMID 10827174.
  • Nakamura H, Fujii Y, Inoki I, Sugimoto K, Tanzawa K, Matsuki H, Miura R, Yamaguchi Y, Okada Y (Dec 2000). "Brevican is degraded by matrix metalloproteinases and aggrecanase-1 (ADAMTS4) at different sites". The Journal of Biological Chemistry. 275 (49): 38885–90. doi:10.1074/jbc.M003875200. PMID 10986281.
  • Mizui Y, Yamazaki K, Kuboi Y, Sagane K, Tanaka I (Sep 2000). "Characterization of 5'-flanking region of human aggrecanase-1 (ADAMTS4) gene". Molecular Biology Reports. 27 (3): 167–73. doi:10.1023/A:1007253930568. PMID 11254106.
  • Sandy JD, Westling J, Kenagy RD, Iruela-Arispe ML, Verscharen C, Rodriguez-Mazaneque JC, Zimmermann DR, Lemire JM, Fischer JW, Wight TN, Clowes AW (Apr 2001). "Versican V1 proteolysis in human aorta in vivo occurs at the Glu441-Ala442 bond, a site that is cleaved by recombinant ADAMTS-1 and ADAMTS-4". The Journal of Biological Chemistry. 276 (16): 13372–8. doi:10.1074/jbc.M009737200. PMID 11278559.
  • Gao G, Westling J, Thompson VP, Howell TD, Gottschall PE, Sandy JD (Mar 2002). "Activation of the proteolytic activity of ADAMTS4 (aggrecanase-1) by C-terminal truncation". The Journal of Biological Chemistry. 277 (13): 11034–41. doi:10.1074/jbc.M107443200. PMID 11796708.
  • Yamanishi Y, Boyle DL, Clark M, Maki RA, Tortorella MD, Arner EC, Firestein GS (Feb 2002). "Expression and regulation of aggrecanase in arthritis: the role of TGF-beta". Journal of Immunology. 168 (3): 1405–12. doi:10.4049/jimmunol.168.3.1405. PMID 11801682.
  • Westling J, Fosang AJ, Last K, Thompson VP, Tomkinson KN, Hebert T, McDonagh T, Collins-Racie LA, LaVallie ER, Morris EA, Sandy JD (May 2002). "ADAMTS4 cleaves at the aggrecanase site (Glu373-Ala374) and secondarily at the matrix metalloproteinase site (Asn341-Phe342) in the aggrecan interglobular domain". The Journal of Biological Chemistry. 277 (18): 16059–66. doi:10.1074/jbc.M108607200. PMID 11854269.
  • Malfait AM, Liu RQ, Ijiri K, Komiya S, Tortorella MD (Jun 2002). "Inhibition of ADAM-TS4 and ADAM-TS5 prevents aggrecan degradation in osteoarthritic cartilage". The Journal of Biological Chemistry. 277 (25): 22201–8. doi:10.1074/jbc.M200431200. PMID 11956193.

External links

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