ADAMTS4

Last updated
ADAMTS4
2RJP.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases ADAMTS4 , ADAMTS-2, ADAMTS-4, ADMP-1, ADAM metallopeptidase with thrombospondin type 1 motif 4
External IDs OMIM: 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 Mb Chr 1: 171.08 – 171.09 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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

Contents

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

Related Research Articles

<span class="mw-page-title-main">ADAMTS5</span> Protein-coding gene in the species Homo sapiens

A disintegrin and metalloproteinase with thrombospondin motifs 5 also known as ADAMTS5 is an enzyme that in humans is encoded by the ADAMTS5 gene.

<span class="mw-page-title-main">ADAMTS13</span> Metalloprotease enzyme

ADAMTS13 —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 reduces thrombus formation.

<span class="mw-page-title-main">ADAMTS2</span> Protein-coding gene in the species Homo sapiens

A disintegrin and metalloproteinase with thrombospondin motifs 2 (ADAM-TS2) also known as procollagen I N-proteinase is an enzyme that in humans is encoded by the ADAMTS2 gene.

<span class="mw-page-title-main">Thrombospondin 1</span> Protein-coding gene in the species Homo sapiens

Thrombospondin 1, abbreviated as THBS1, is a protein that in humans is encoded by the THBS1 gene.

<span class="mw-page-title-main">Aggrecan</span>

Aggrecan (ACAN), also known as cartilage-specific proteoglycan core protein (CSPCP) or chondroitin sulfate proteoglycan 1, is a protein that in humans is encoded by the ACAN gene. This gene is a member of the lectican (chondroitin sulfate proteoglycan) family. The encoded protein is an integral part of the extracellular matrix in cartilagenous tissue and it withstands compression in cartilage.

Aggrecanases are extracellular proteolytic enzymes that are members of the ADAMTS family. Aggrecanases act on large proteoglycans known as aggrecans, which are components of connective tissues such as cartilage. The inappropriate activity of aggrecanase is a mechanism by which cartilage degradation occurs in diseases such as arthritis. At least two forms of aggrecanase exist in humans: ADAMTS4 or aggrecanase-1 and ADAMTS5 or aggrecanase-2. Both proteins contain thrombospondin (TS) motifs required for proper recognition of substrates. Although both proteins can cleave the substrate aggrecan at the same position, they differ in kinetics and in secondary cleavage sites.

<span class="mw-page-title-main">Matrix metallopeptidase 13</span> Protein-coding gene in the species Homo sapiens

Collagenase 3 is an enzyme that in humans is encoded by the MMP13 gene. It is a member of the matrix metalloproteinase (MMP) family. Like most MMPs, it is secreted as an inactive pro-form. MMP-13 has an predicted molecular weight around 54 kDa. It is activated once the pro-domain is cleaved, leaving an active enzyme composed of the catalytic domain and the hemopexin-like domain PDB: 1PEX​. Although the actual mechanism has not been described, the hemopexin domain participates in collagen degradation, the catalytic domain alone being particularly inefficient in collagen degradation. During embryonic development, MMP-13 is expressed in the skeleton as required for restructuring the collagen matrix for bone mineralization. In pathological situations it is highly overexpressed; this occurs in human carcinomas, rheumatoid arthritis and osteoarthritis.

<span class="mw-page-title-main">ADAMTS1</span> Protein-coding gene in the species Homo sapiens

A disintegrin and metalloproteinase with thrombospondin motifs 1 is an enzyme that in humans is encoded by the ADAMTS1 gene.

<span class="mw-page-title-main">MMP19</span> Protein-coding gene in the species Homo sapiens

Matrix metalloproteinase-19 (MMP-19) also known as matrix metalloproteinase RASI is an enzyme that in humans is encoded by the MMP19 gene.

<span class="mw-page-title-main">Brevican</span> Protein-coding gene in the species Homo sapiens

Brevican core protein is a protein that in humans is encoded by the BCAN gene. Brevican is a member of the lectican protein family.

ADAMTS is a family of multidomain extracellular protease enzymes. 19 members of this family have been identified in humans, the first of which, ADAMTS1, was described in 1997. Known functions of the ADAMTS proteases include processing of procollagens and von Willebrand factor as well as cleavage of aggrecan, versican, brevican and neurocan, making them key remodeling enzymes of the extracellular matrix. They have been demonstrated to have important roles in connective tissue organization, coagulation, inflammation, arthritis, angiogenesis and cell migration. Homologous subfamily of ADAMTSL (ADAMTS-like) proteins, which lack enzymatic activity, has also been described. Most cases of thrombotic thrombocytopenic purpura arise from autoantibody-mediated inhibition of ADAMTS13.

<span class="mw-page-title-main">ADAMTS8</span> Protein-coding gene in the species Homo sapiens

A disintegrin and metalloproteinase with thrombospondin motifs 8 is an enzyme that in humans is encoded by the ADAMTS8 gene.

<span class="mw-page-title-main">ADAMTS9</span> Protein-coding gene in the species Homo sapiens

A disintegrin and metalloproteinase with thrombospondin motifs 9 is an enzyme that in humans is encoded by the ADAMTS9 gene.

<span class="mw-page-title-main">ADAMTS10</span> Protein-coding gene in the species Homo sapiens

A disintegrin and metalloproteinase with thrombospondin motifs 10 is an enzyme that in humans is encoded by the ADAMTS10 gene.

<span class="mw-page-title-main">ADAMTSL1</span> Protein-coding gene in the species Homo sapiens

ADAMTS-like protein 1 is a protein that in humans is encoded by the ADAMTSL1 gene.

<span class="mw-page-title-main">ADAMTS3</span> Protein-coding gene in the species Homo sapiens

A disintegrin and metalloproteinase with thrombospondin motifs 3 is an enzyme that in humans is encoded by the ADAMTS3 gene. The protein encoded by this gene is the major procollagen II N-propeptidase.

<span class="mw-page-title-main">ADAMTS12</span> Protein-coding gene in the species Homo sapiens

A disintegrin and metalloproteinase with thrombospondin motifs 12 is an enzyme that in humans is encoded by the ADAMTS12 gene.

Angiogenesis is the process of forming new blood vessels from existing blood vessels, formed in vasculogenesis. It is a highly complex process involving extensive interplay between cells, soluble factors, and the extracellular matrix (ECM). Angiogenesis is critical during normal physiological development, but it also occurs in adults during inflammation, wound healing, ischemia, and in pathological conditions such as rheumatoid arthritis, hemangioma, and tumor growth. Proteolysis has been indicated as one of the first and most sustained activities involved in the formation of new blood vessels. Numerous proteases including matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase domain (ADAM), a disintegrin and metalloproteinase domain with throbospondin motifs (ADAMTS), and cysteine and serine proteases are involved in angiogenesis. This article focuses on the important and diverse roles that these proteases play in the regulation of angiogenesis.

ADAMTS-4 endopeptidase is an enzyme. This enzyme catalyses the following chemical reaction

A disintegrin and metalloproteinase with thrombospondin motifs 7 (ADAMTS7) is an enzyme that in humans is encoded by the ADAMTS7 gene on chromosome 15. It is ubiquitously expressed in many tissues and cell types. This enzyme catalyzes the degradation of cartilage oligomeric matrix protein (COMP) degradation. ADAMTS7 has been associated with cancer and arthritis in multiple tissue types. The ADAMTS7 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000158859 - Ensembl, May 2017
  2. 1 2 3 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.
  6. ↑ "Entrez Gene: ADAMTS4 ADAM metallopeptidase with thrombospondin type 1 motif, 4".
  7. 1 2 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.

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