ADAMTS1

File:3D_structure_of_ADAMTS1.png

This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motif) 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 protein encoded by this gene contains two disintegrin loops and three C-terminal TS motifs and has anti-angiogenic activity.

ADAMTS1 is a metalloproteinase whose structure includes several critical domains that enable its enzymatic function. These include a metalloproteinase domain, disintegrin-like domain, thrombospondin type 1 repeats (TSRs), and C-terminal regions such as spacer and cysteine-rich domains. Spacer domains are essential for substrate binding and contain clusters of positively charged residues that interact with negatively charged substrates such as versican and aggrecan.{{Cite journal | vauthors = Qi Y, Yamamoto K, Lee K, Ahnström J, Santamaria S, Minns AF | title = The C-terminal domains of ADAMTS1 contain exosites involved in its proteoglycanase activity | journal = The Journal of Biological Chemistry | volume = 299 | issue = 4 | pages = 103048 | date = April 2023 | pmid = 36813235 | pmc = 10033314 | doi = 10.1016/j.jbc.2023.103048 | doi-access = free | language = en }} Cysteine residues contribute to the structural stability of ADAMTS1, and deletion of this domain significantly reduces versicanase activity.

Thrombospondin type 1 repeats facilitate binding to sulfated glycosaminoglycans, including heparin and heparan sulfate, which helps anchor ADAMTS1 within the extracellular matrix (ECM).{{Cite journal | vauthors = Matsushima K, Kuno K | title = ADAMTS-1 Protein Anchors at the Extracellular Matrix through the Thrombospondin Type I Motifs and Its Spacing Region * | journal = The Journal of Biological Chemistry | volume = 273 | issue = 22 | pages = 13912–13917 | date = 1998-05-29 | pmid = 9593739 | doi = 10.1074/jbc.273.22.13912 | doi-access = free | language = English | issn = 0021-9258 }} This positioning is important for efficient proteolytic activity on ECM substrates.

ADAMTS1 plays a key enzymatic role in remodeling the extracellular matrix (ECM) by cleaving proteoglycans such as versican and aggrecan. These substrates are major components of the ECM and are particularly important for cartilage development and maintaining structural integrity.{{Cite journal | vauthors = Watanabe H | title = Aggrecan and versican: two brothers close or apart | journal = American Journal of Physiology-Cell Physiology | volume = 322 | issue = 5 | pages = C967–C976 | date = May 2022 | pmid = 35385326 | doi = 10.1152/ajpcell.00081.2022 | url = https://journals.physiology.org/doi/full/10.1152/ajpcell.00081.2022 | issn = 0363-6143 }} By targeting specific cleavage sites, ADAMTS1 regulates ECM composition, influencing cell migration, differentiation, and tissue remodeling.

This enzymatic activity is critical for several physiological processes, including fertilization, cardiovascular development, and cancer progression. Its ability to remodel ECM components is central to maintaining tissue architecture and facilitating intercellular signaling.

More broadly, ADAMTS proteases contribute to ECM remodeling necessary for tissue morphogenesis and germ cell development in both sexes. These structural rearrangements allow for proper ligand-receptor interactions that support coordinated tissue growth and regression.{{Cite journal | vauthors = Hastings G, Ortega MA, Lane TF, Oikemus S, Lombardo M, Iruela-Arispe ML, Vázquez F | title = METH-1, a Human Ortholog of ADAMTS-1, and METH-2 Are Members of a New Family of Proteins with Angio-inhibitory Activity | journal = The Journal of Biological Chemistry | volume = 274 | issue = 33 | pages = 23349–23357 | date = August 1999 | pmid = 10438512 | doi = 10.1074/jbc.274.33.23349 | doi-access = free | language = en }}

During folliculogenesis, ADAMTS1, along with ADAMTS4 and ADAMTS16, is upregulated by follicle-stimulating hormone (FSH), promoting follicle growth and survival.{{Cite journal | vauthors = Brown HM, Dunning KR, Russell DL | title = ADAMTS proteases in fertility | journal = Matrix Biology | volume = 44-46 | pages = 54–63 | date = 2015-05-01 | pmid = 25818315 | doi = 10.1016/j.matbio.2015.03.007 | url = https://linkinghub.elsevier.com/retrieve/pii/S0945053X1500058X | series = Metalloproteinases in Extracellular Matrix Biology | issn = 0945-053X | doi-access = free }} ADAMTS1 is predominantly expressed in granulosa cells, where it is essential for follicular integrity. In its absence, granulosa cells progressively degenerate, leading to follicular breakdown. However, the oocytes remain intact and accumulate within the ovarian stroma.

Expression of the ADAMTS1 gene has been associated with various inflammatory processes and the development of cancer cachexia.{{cite web | title = Entrez Gene: ADAMTS1 ADAM metallopeptidase with thrombospondin type 1 motif, 1 | url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9510 }}

Altered expression or activity of ADAMTS proteases, including ADAMTS1, has been linked to reproductive disorders such as polycystic ovary syndrome (PCOS). These disruptions may impair ECM remodeling, which is crucial for proper follicular development and ovulation, contributing to the pathophysiology of PCOS and related fertility issues.

ADAMTS1 has been shown to interact with Vascular endothelial growth factor A.{{cite journal | vauthors = Luque A, Carpizo DR, Iruela-Arispe ML | title = ADAMTS1/METH1 inhibits endothelial cell proliferation by direct binding and sequestration of VEGF165 | journal = Journal of Biological Chemistry | volume = 278 | issue = 26 | pages = 23656–23665 | date = June 2003 | pmid = 12716911 | doi = 10.1074/jbc.M212964200 | doi-access = free }}

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• {{cite journal | vauthors = Tang BL, Hong W | title = ADAMTS: a novel family of proteases with an ADAM protease domain and thrombospondin 1 repeats | journal = FEBS Letters | volume = 445 | issue = 2–3 | pages = 223–225 | date = Feb 1999 | pmid = 10094461 | doi = 10.1016/S0014-5793(99)00119-2 | s2cid = 37955930 | doi-access = free | bibcode = 1999FEBSL.445..223T }}
• {{cite journal | vauthors = Hirohata S | title = [ADAMTS family--new extracellular matrix degrading enzyme] | journal = Seikagaku. The Journal of Japanese Biochemical Society | volume = 73 | issue = 11 | pages = 1333–1337 | date = Nov 2001 | pmid = 11831030 }}
• {{cite journal | vauthors = Kuno K, Kanada N, Nakashima E, Fujiki F, Ichimura F, Matsushima K | title = Molecular cloning of a gene encoding a new type of metalloproteinase-disintegrin family protein with thrombospondin motifs as an inflammation associated gene | journal = Journal of Biological Chemistry | volume = 272 | issue = 1 | pages = 556–562 | date = Jan 1997 | pmid = 8995297 | doi = 10.1074/jbc.272.1.556 | doi-access = free }}
• {{cite journal | vauthors = Kuno K, Matsushima K | title = ADAMTS-1 protein anchors at the extracellular matrix through the thrombospondin type I motifs and its spacing region | journal = Journal of Biological Chemistry | volume = 273 | issue = 22 | pages = 13912–13917 | date = May 1998 | pmid = 9593739 | doi = 10.1074/jbc.273.22.13912 | doi-access = free }}
• {{cite journal | vauthors = Kuno K, Terashima Y, Matsushima K | title = ADAMTS-1 is an active metalloproteinase associated with the extracellular matrix | journal = Journal of Biological Chemistry | volume = 274 | issue = 26 | pages = 18821–18826 | date = Jun 1999 | pmid = 10373500 | doi = 10.1074/jbc.274.26.18821 | doi-access = free }}
• {{cite journal | vauthors = Nagase T, Kikuno R, Ishikawa KI, Hirosawa M, Ohara O | title = Prediction of the coding sequences of unidentified human genes. XVI. The complete sequences of 150 new cDNA clones from brain which code for large proteins in vitro | journal = DNA Research : An International Journal for Rapid Publication of Reports on Genes and Genomes | volume = 7 | issue = 1 | pages = 65–73 | date = Feb 2000 | pmid = 10718198 | doi = 10.1093/dnares/7.1.65 | doi-access = free }}
• {{cite journal | vauthors = Glienke J, Schmitt AO, Pilarsky C, Hinzmann B, Weiss B, Rosenthal A, Thierauch KH | title = Differential gene expression by endothelial cells in distinct angiogenic states | journal = European Journal of Biochemistry | volume = 267 | issue = 9 | pages = 2820–2830 | date = May 2000 | pmid = 10785405 | doi = 10.1046/j.1432-1327.2000.01325.x | doi-access = free }}
• {{cite journal | vauthors = Shindo T, Kurihara H, Kuno K, Yokoyama H, Wada T, Kurihara Y, Imai T, Wang Y, Ogata M, Nishimatsu H, Moriyama N, Oh-hashi Y, Morita H, Ishikawa T, Nagai R, Yazaki Y, Matsushima K | title = ADAMTS-1: a metalloproteinase-disintegrin essential for normal growth, fertility, and organ morphology and function | journal = The Journal of Clinical Investigation | volume = 105 | issue = 10 | pages = 1345–1352 | date = May 2000 | pmid = 10811842 | pmc = 315464 | doi = 10.1172/JCI8635 }}
• {{cite journal | vauthors = Kuno K, Okada Y, Kawashima H, Nakamura H, Miyasaka M, Ohno H, Matsushima K | title = ADAMTS-1 cleaves a cartilage proteoglycan, aggrecan | journal = FEBS Letters | volume = 478 | issue = 3 | pages = 241–245 | date = Aug 2000 | pmid = 10930576 | doi = 10.1016/S0014-5793(00)01854-8 | s2cid = 32699689 | doi-access = free | bibcode = 2000FEBSL.478..241K }}
• {{cite journal | vauthors = Sandy JD, Westling J, Kenagy RD, Iruela-Arispe ML, Verscharen C, Rodriguez-Mazaneque JC, Zimmermann DR, Lemire JM, Fischer JW, Wight TN, Clowes AW | title = 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 | journal = Journal of Biological Chemistry | volume = 276 | issue = 16 | pages = 13372–13378 | date = Apr 2001 | pmid = 11278559 | doi = 10.1074/jbc.M009737200 | doi-access = free }}
• {{cite journal | vauthors = Wei P, Zhao YG, Zhuang L, Hurst DR, Ruben S, Sang QX | title = Protein engineering and properties of human metalloproteinase and thrombospondin 1 | journal = Biochemical and Biophysical Research Communications | volume = 293 | issue = 1 | pages = 478–488 | date = Apr 2002 | pmid = 12054626 | doi = 10.1016/S0006-291X(02)00255-3 }}
• {{cite journal | vauthors = Rodriguez-Manzaneque JC, Westling J, Thai SN, Luque A, Knauper V, Murphy G, Sandy JD, Iruela-Arispe ML | title = ADAMTS1 cleaves aggrecan at multiple sites and is differentially inhibited by metalloproteinase inhibitors | journal = Biochemical and Biophysical Research Communications | volume = 293 | issue = 1 | pages = 501–508 | date = Apr 2002 | pmid = 12054629 | doi = 10.1016/S0006-291X(02)00254-1 }}
• {{cite journal | vauthors = Luque A, Carpizo DR, Iruela-Arispe ML | title = ADAMTS1/METH1 inhibits endothelial cell proliferation by direct binding and sequestration of VEGF165 | journal = Journal of Biological Chemistry | volume = 278 | issue = 26 | pages = 23656–23665 | date = Jun 2003 | pmid = 12716911 | doi = 10.1074/jbc.M212964200 | doi-access = free }}
• {{cite journal | vauthors = Russell DL, Doyle KM, Ochsner SA, Sandy JD, Richards JS | title = Processing and localization of ADAMTS-1 and proteolytic cleavage of versican during cumulus matrix expansion and ovulation | journal = Journal of Biological Chemistry | volume = 278 | issue = 43 | pages = 42330–42339 | date = Oct 2003 | pmid = 12907688 | doi = 10.1074/jbc.M300519200 | doi-access = free }}

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• The MEROPS online database for peptidases and their inhibitors: [http://merops.sanger.ac.uk/cgi-bin/merops.cgi?id=M12.222 M12.222]
• [http://AtlasGeneticsOncology.org/Genes/ADAMTS1ID574ch21q21.html ADAMTS1] on the Atlas of Genetics and Oncology
• {{UCSC gene info|ADAMTS1}}
• {{PDBe-KB2|Q9UHI8|A disintegrin and metalloproteinase with thrombospondin motifs 1}}

{{Metalloproteinases}}

Category:ADAMTS

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