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ADAMTS1

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ADAMTS1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesADAMTS1, C3-C5, METH1, ADAM metallopeptidase with thrombospondin type 1 motif 1
External IDsOMIM: 605174; MGI: 109249; HomoloGene: 21381; GeneCards: ADAMTS1; OMA:ADAMTS1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

9510

11504

Ensembl

ENSG00000154734

ENSMUSG00000022893

UniProt

Q9UHI8

P97857

RefSeq (mRNA)

NM_006988

NM_009621

RefSeq (protein)

NP_008919

NP_033751

Location (UCSC)Chr 21: 26.84 – 26.85 MbChr 16: 85.59 – 85.6 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

A disintegrin and metalloproteinase with thrombospondin motifs 1 is an enzyme that in humans is encoded by the ADAMTS1 gene.[5][6]

Structure

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The AlphaFold predicted structure of ADAMTS1. The TSP type 1 domains (cyan) are located at residues 559–614, 854–905, and 908–967. The spacer region (red) spans residues 725–849, while the Peptidase M12B domain (medium blue) is found at 467–558. The cysteine switch (white) is at residues 196–203, and the active site (green) is at position 402.[7]

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.[6]

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.[8] Cysteine residues contribute to the structural stability of ADAMTS1, and deletion of this domain significantly reduces versicanase activity.[8] Thrombospondin type 1 repeats facilitate binding to sulfated glycosaminoglycans, including heparin and heparan sulfate, which helps anchor ADAMTS1 within the extracellular matrix (ECM).[9] This positioning is important for efficient proteolytic activity on ECM substrates.

Function

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ADAMTS1 plays a key enzymatic role in remodeling the extracellular matrix (ECM) by cleaving proteoglycans such as versican and aggrecan.[8] These substrates are major components of the ECM and are particularly important for cartilage development and maintaining structural integrity.[10] By targeting specific cleavage sites, ADAMTS1 regulates ECM composition, influencing cell migration, differentiation, and tissue remodeling.[10]

This enzymatic activity is critical for several physiological processes, including fertilization, cardiovascular development, and cancer progression.[8] 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.[11]

During folliculogenesis, ADAMTS1, along with ADAMTS4 and ADAMTS16, is upregulated by follicle-stimulating hormone (FSH), promoting follicle growth and survival.[12] 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.[12]

Clinical significance

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Expression of the ADAMTS1 gene has been associated with various inflammatory processes and the development of cancer cachexia.[6] Altered expression or activity of ADAMTS proteases, including ADAMTS1, has been linked to reproductive disorders such as polycystic ovary syndrome (PCOS).[12] 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.

Interactions

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ADAMTS1 has been shown to interact with Vascular endothelial growth factor A.[13]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000154734 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000022893 – 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. ^ Vazquez F, Hastings G, Ortega MA, Lane TF, Oikemus S, Lombardo M, et al. (September 1999). "METH-1, a human ortholog of ADAMTS-1, and METH-2 are members of a new family of proteins with angio-inhibitory activity". Journal of Biological Chemistry. 274 (33): 23349–23357. doi:10.1074/jbc.274.33.23349. PMID 10438512.
  6. ^ a b c "Entrez Gene: ADAMTS1 ADAM metallopeptidase with thrombospondin type 1 motif, 1".
  7. ^ "Q9UHI8 · ATS1_HUMAN".
  8. ^ a b c d Qi Y, Yamamoto K, Lee K, Ahnström J, Santamaria S, Minns AF (April 2023). "The C-terminal domains of ADAMTS1 contain exosites involved in its proteoglycanase activity". The Journal of Biological Chemistry. 299 (4): 103048. doi:10.1016/j.jbc.2023.103048. PMC 10033314. PMID 36813235.
  9. ^ Matsushima K, Kuno K (1998-05-29). "ADAMTS-1 Protein Anchors at the Extracellular Matrix through the Thrombospondin Type I Motifs and Its Spacing Region *". The Journal of Biological Chemistry. 273 (22): 13912–13917. doi:10.1074/jbc.273.22.13912. ISSN 0021-9258. PMID 9593739.
  10. ^ a b Watanabe H (May 2022). "Aggrecan and versican: two brothers close or apart". American Journal of Physiology-Cell Physiology. 322 (5): C967 – C976. doi:10.1152/ajpcell.00081.2022. ISSN 0363-6143. PMID 35385326.
  11. ^ Hastings G, Ortega MA, Lane TF, Oikemus S, Lombardo M, Iruela-Arispe ML, et al. (August 1999). "METH-1, a Human Ortholog of ADAMTS-1, and METH-2 Are Members of a New Family of Proteins with Angio-inhibitory Activity". The Journal of Biological Chemistry. 274 (33): 23349–23357. doi:10.1074/jbc.274.33.23349. PMID 10438512.
  12. ^ a b c Brown HM, Dunning KR, Russell DL (2015-05-01). "ADAMTS proteases in fertility". Matrix Biology. Metalloproteinases in Extracellular Matrix Biology. 44–46: 54–63. doi:10.1016/j.matbio.2015.03.007. ISSN 0945-053X. PMID 25818315.
  13. ^ Luque A, Carpizo DR, Iruela-Arispe ML (June 2003). "ADAMTS1/METH1 inhibits endothelial cell proliferation by direct binding and sequestration of VEGF165". Journal of Biological Chemistry. 278 (26): 23656–23665. doi:10.1074/jbc.M212964200. PMID 12716911.

Further reading

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