ADAMTS4
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesADAMTS4, ADAMTS-2, ADAMTS-4, ADMP-1, ADAM metallopeptidase with thrombospondin type 1 motif 4
External IDsOMIM: 603876 MGI: 1339949 HomoloGene: 36169 GeneCards: ADAMTS4
Orthologs
SpeciesHumanMouse
Entrez

9507

240913

Ensembl

ENSG00000158859

ENSMUSG00000006403

UniProt

O75173

Q8BNJ2

RefSeq (mRNA)

NM_005099
NM_001320336

NM_172845

RefSeq (protein)

NP_001307265
NP_005090

NP_766433

Location (UCSC)Chr 1: 161.18 – 161.2 MbChr 1: 171.08 – 171.09 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

A disintegrin and metalloproteinase with thrombospondin motifs 4 is an enzyme that in humans is encoded by the ADAMTS4 gene.[5]

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.[6]

Structure

ADAMTS4 is the shortest known ADAMTS, lacking the C-terminal domain and is the only non-glycosylated ADAMTS.[7] 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.[8]

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)[9] and this inhibition can be enhanced in the presence of aggrecan.[10] In addition to TIMP3, it can also be inhibited by calcium pentosan polysulfate.[11]

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.[7]

Clinical Significance

ADAMTS4 (and ADAMTS5) are the major proteinases responsible for the degradation of proteoglycans in articular cartilage in osteoarthritis.[12] 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

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000158859 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000006403 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ 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. S2CID 37955930.
  6. ^ "Entrez Gene: ADAMTS4 ADAM metallopeptidase with thrombospondin type 1 motif, 4".
  7. ^ a b 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.
  8. ^ 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.
  9. ^ 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.
  10. ^ 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.
  11. ^ 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. S2CID 10240795.
  12. ^ 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

External links

Proteases: metalloendopeptidases (EC 3.4.24)
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