ADAMTS7

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A disintegrin and metalloproteinase with thrombospondin motifs 7 (ADAMTS7) is an enzyme that in humans is encoded by the ADAMTS7 gene on chromosome 15. [1] It is ubiquitously expressed in many tissues and cell types. [2] This enzyme catalyzes the degradation of cartilage oligomeric matrix protein (COMP). [3] ADAMTS7 has been associated with cancer and arthritis in multiple tissue types. [4] [5] The ADAMTS7 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease. [6]

Contents

Structure

Gene

The ADAMTS7 gene resides on chromosome 15 at the band 15q24.2 and contains 25 exons. [1]

Protein

This 1686-amino acid protein belongs to the ADAMTS family and is one of 19 members known in humans. As an ADAMTS protein, ADAMTS7 contains a shared proteinase domain and an ancillary domain. The proteinase domain can be further divided into a signal peptide, a prodomain, a metalloproteinase domain, and a disintegrin-like domain. [7] In particular, the metalloproteinase domain contains a cysteine-switch motif in its binding site for binding the catalytic zinc ion (Zn2+). [8] A pharmacophore model consisting of four hydrogen bond donor sites and three hydrogen bond acceptor sites was proposed for this domain. Unlike the proteinase domain, the ancillary domain varies by ADAMTS protein and includes any number of thrombospondin (TSP) type 1 motifs, one cysteine-rich and spacer domain, and other domains specific to certain ADAMTS proteins. [7] ADAMTS7 in particular possesses 8 TSP type 1 motifs which, together with its spacer domain, participate in the protein’s tight interaction with the extracellular matrix. [8]

Function

ADAMTS7 was identified in a yeast two-hybrid screen using epidermal growth factor (EGF) domain of COMP as the bait. As a metalloproteinase, ADAMTS7 utilizes Zn2+ to catalyze its proteolytic function for COMP degradation. [3]

In vascular smooth muscle cell (VSMC), ADAMTS7 mediates VSMC migration, which plays an essential role during the development of atherosclerosis and restenosis. [9] Adamts7 deficiency in both the Ldlr−/− and Apoe−/− hyperlipidemic mouse models markedly attenuates formation of atherosclerotic lesions; furthermore, wire-injury experiments in the Adamts7−/− mouse show reduced neointima formation. [10] The association of ADAMTS7 with atherosclerosis suggests that inhibition of ADAMTS7 should be atheroprotective in humans. [10]

Clinical Significance

A negative correlation between the expression levels of specific miRNAs and ADAMTS7 is observed in normal tissues but not in disease tissues, implying an altered miRNA-target interaction in the disease state. Accordingly, expression profiles of these miRNAs and ADAMTS7 may be useful diagnostic tools to differentiate cancer and lichen planus from normal tissues. [11] ADAMTS7 has also been identified as a putative oncogene and reported to be mutated exclusively in Asians, which may have implications for the prevention and treatment of hepatocellular carcinoma. [4] In addition, ADAMTS7 plays a crucial role in the pathogenesis of arthritis. [5] For example, the FGF2/p65/miR-105/Runx2/ADAMTS axis is reportedly involved in osteoarthritis (OA) pathogenesis. [12] Specifically, ADAMTS7 forms a positive feedback loop with tumour necrosis factor (TNF)-α in the pathogenesis of OA. [13]

Clinical Marker

Genome-wide association studies identified ADAMTS7 as a risk locus for coronary artery disease. Studies have been carried on classification of ADAMTS7 binding site, which may serve as the first step toward developing a new therapeutic target for coronary artery disease. [7] Significant associations for coronary artery calcification with SNPs in ADAMTS7 has also been found in Hispanics. [14] Additionally, a multi-locus genetic risk score study based on a combination of 27 loci, including the ADAMTS7 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22). [6]

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 reduce 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">ADAM (protein)</span>

ADAMs are a family of single-pass transmembrane and secreted metalloendopeptidases. All ADAMs are characterized by a particular domain organization featuring a pro-domain, a metalloprotease, a disintegrin, a cysteine-rich, an epidermal-growth factor like and a transmembrane domain, as well as a C-terminal cytoplasmic tail. Nonetheless, not all human ADAMs have a functional protease domain, which indicates that their biological function mainly depends on protein–protein interactions. Those ADAMs which are active proteases are classified as sheddases because they cut off or shed extracellular portions of transmembrane proteins. For example, ADAM10 can cut off part of the HER2 receptor, thereby activating it. ADAM genes are found in animals, choanoflagellates, fungi and some groups of green algae. Most green algae and all land plants likely lost ADAM proteins.

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">ADAMTS4</span> Protein-coding gene in the species Homo sapiens

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

<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 a 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">ADAM22</span> Enzyme found in humans

Disintegrin and metalloproteinase domain-containing protein 22, also known as ADAM22, is an enzyme that in humans is encoded by the ADAM22 gene.

<span class="mw-page-title-main">ADAMTSL4</span> Protein-coding gene in the species Homo sapiens

ADAMTS-like protein 4 is a protein that in humans is encoded by the ADAMTSL4 gene.

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.

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

Phosphatase and actin regulator 1 (PHACTR1) is a protein that in humans is encoded by the PHACTR1 gene on chromosome 6. It is most significantly expressed in the globus pallidus of the brain. PHACTR1 is an actin and protein phosphatase 1 (PP1) binding protein that binds actin and regulates the reorganization of the actin cytoskeleton. This protein has been associated with coronary artery disease and migraines through genome-wide association studies. The PHACTR1 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.

<span class="mw-page-title-main">ADAMTS6</span> Protein in humans

ADAM metallopeptidase with thrombospondin type 1 motif 6 is a protein that in humans is encoded by the ADAMTS6 gene.

CKLF-like MARVEL transmembrane domain-containing 5 (CMTM5), previously termed chemokine-like factor superfamily 5, designates any one of the six protein isoforms encoded by six different alternative splices of its gene, CMTM5; CMTM5-v1 is the most studied of these isoforms. The CMTM5 gene is located in band 11.2 on the long arm of chromosome 14.

References

  1. 1 2 "ADAMTS7 ADAM metallopeptidase with thrombospondin type 1 motif 7 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2016-10-06.
  2. ↑ "BioGPS - your Gene Portal System". biogps.org. Retrieved 2016-10-06.
  3. 1 2 Liu, Chuan-Ju; Kong, Wei; Ilalov, Kiril; Yu, Shuang; Xu, Ke; Prazak, Lisa; Fajardo, Marc; Sehgal, Bantoo; Di Cesare, Paul E. (2006-05-01). "ADAMTS-7: a metalloproteinase that directly binds to and degrades cartilage oligomeric matrix protein". FASEB Journal. 20 (7): 988–990. doi: 10.1096/fj.05-3877fje . ISSN   1530-6860. PMC   1483927 . PMID   16585064.
  4. 1 2 Yao, Song; Johnson, Christopher; Hu, Qiang; Yan, Li; Liu, Biao; Ambrosone, Christine B.; Wang, Jianmin; Liu, Song (2016-05-26). "Differences in somatic mutation landscape of hepatocellular carcinoma in Asian American and European American populations". Oncotarget. 7 (26): 40491–40499. doi:10.18632/oncotarget.9636. ISSN   1949-2553. PMC   5130022 . PMID   27246981.
  5. 1 2 Zhang, Yuying; Lin, Jiqiang; Wei, Fanhua (2015-01-01). "The Function and Roles of ADAMTS-7 in Inflammatory Diseases". Mediators of Inflammation. 2015: 801546. doi: 10.1155/2015/801546 . ISSN   1466-1861. PMC   4677222 . PMID   26696755.
  6. 1 2 Mega, Jessica L.; Stitziel, Nathan O.; Smith, J. Gustav; Chasman, Daniel I.; Caulfield, Mark J.; Devlin, James J.; Nordio, Francesco; Hyde, Craig L.; Cannon, Christopher P. (2015-06-06). "Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials". Lancet. 385 (9984): 2264–2271. doi:10.1016/S0140-6736(14)61730-X. ISSN   1474-547X. PMC   4608367 . PMID   25748612.
  7. 1 2 3 Müller, Michaela; Kessler, Thorsten; Schunkert, Heribert; Erdmann, Jeanette; Tennstedt, Stephanie (2016-03-11). "Classification of ADAMTS binding sites: The first step toward selective ADAMTS7 inhibitors". Biochemical and Biophysical Research Communications. 471 (3): 380–385. doi:10.1016/j.bbrc.2016.02.025. ISSN   1090-2104. PMID   26872430.
  8. 1 2 "ADAMTS7 - A disintegrin and metalloproteinase with thrombospondin motifs 7 precursor - Homo sapiens (Human) - ADAMTS7 gene & protein". www.uniprot.org. Retrieved 2016-10-06.
  9. ↑ Wang, Li; Zheng, Jingang; Bai, Xue; Liu, Bo; Liu, Chuan-Ju; Xu, Qingbo; Zhu, Yi; Wang, Nanping; Kong, Wei (2009-03-13). "ADAMTS-7 mediates vascular smooth muscle cell migration and neointima formation in balloon-injured rat arteries". Circulation Research. 104 (5): 688–698. doi: 10.1161/CIRCRESAHA.108.188425 . ISSN   1524-4571. PMID   19168437.
  10. 1 2 Bauer, Robert C.; Tohyama, Junichiro; Cui, Jian; Cheng, Lan; Yang, Jifu; Zhang, Xuan; Ou, Kristy; Paschos, Georgios K.; Zheng, X. Long (2015-03-31). "Knockout of Adamts7, a novel coronary artery disease locus in humans, reduces atherosclerosis in mice". Circulation. 131 (13): 1202–1213. doi:10.1161/CIRCULATIONAHA.114.012669. ISSN   1524-4539. PMC   4382454 . PMID   25712206.
  11. ↑ Roy, Roshni; Singh, Richa; Chattopadhyay, Esita; Ray, Anindita; Sarkar, Navonil De; Aich, Ritesh; Paul, Ranjan Rashmi; Pal, Mousumi; Roy, Bidyut (2016-11-15). "MicroRNA and target gene expression based clustering of oral cancer, precancer and normal tissues". Gene. 593 (1): 58–63. doi:10.1016/j.gene.2016.08.011. ISSN   1879-0038. PMID   27515006.
  12. ↑ Ji, Quanbo; Xu, Xiaojie; Xu, Yameng; Fan, Zhongyi; Kang, Lei; Li, Ling; Liang, Yingchun; Guo, Jing; Hong, Tian (2016-06-01). "miR-105/Runx2 axis mediates FGF2-induced ADAMTS expression in osteoarthritis cartilage". Journal of Molecular Medicine. 94 (6): 681–694. doi:10.1007/s00109-016-1380-9. ISSN   1432-1440. PMID   26816250. S2CID   12969036.
  13. ↑ Lai, Yongjie; Bai, Xiaohui; Zhao, Yunpeng; Tian, Qingyun; Liu, Ben; Lin, Edward A.; Chen, Yuqing; Lee, Brendan; Appleton, C. Thomas (2014-08-01). "ADAMTS-7 forms a positive feedback loop with TNF-α in the pathogenesis of osteoarthritis". Annals of the Rheumatic Diseases. 73 (8): 1575–1584. doi:10.1136/annrheumdis-2013-203561. ISSN   1468-2060. PMC   4418017 . PMID   23928557.
  14. ↑ Wand, K.; Straub, M.; Lohmann, C. P.; Mayer, C. S. (2016-02-15). "[Sympathetic ophthalmia : Therapy with steroid-free immunosuppressant azathioprine]". Der Ophthalmologe: Zeitschrift der Deutschen Ophthalmologischen Gesellschaft. 113 (10): 867–869. doi:10.1007/s00347-016-0227-7. ISSN   1433-0423. PMID   26879557. S2CID   24394552.
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