ADAMTS1

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

ADAMTS1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2JIH, 2V4B, 3Q2G, 3Q2H
Identifiers
Aliases	ADAMTS1, C3-C5, METH1, ADAM metallopeptidase with thrombospondin type 1 motif 1
External IDs	OMIM: 605174; MGI: 109249; HomoloGene: 21381; GeneCards: ADAMTS1; OMA:ADAMTS1 - orthologs
Gene location (Human) Chr. Chromosome 21 (human)[1] Band 21q21.3 Start 26,835,755 bp[1] End 26,845,409 bp[1]
Gene location (Mouse) Chr. Chromosome 16 (mouse)[2] Band 16 C3.3|16 48.2 cM Start 85,590,715 bp[2] End 85,600,001 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right ovary left uterine tube vena cava left ovary pericardium gastric mucosa decidua tibial arteries mucosa of urinary bladder ascending aorta Top expressed in iris left lung lobe efferent ductule stroma of bone marrow ciliary body gastrula ascending aorta aortic valve vas deferens decidua More reference expression data BioGPS More reference expression data
Gene ontology Molecular function heparin binding zinc ion binding metal ion binding peptidase activity metalloendopeptidase activity hydrolase activity metallopeptidase activity Cellular component extracellular region basement membrane cytoplasmic vesicle extracellular matrix collagen-containing extracellular matrix Biological process ovulation from ovarian follicle heart trabecula formation kidney development proteolysis integrin-mediated signaling pathway negative regulation of cell population proliferation positive regulation of G1/S transition of mitotic cell cycle positive regulation of vascular associated smooth muscle cell proliferation positive regulation of vascular associated smooth muscle cell migration Sources:Amigo / QuickGO
Orthologs Species Human Mouse 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 Mb Chr 16: 85.59 – 85.6 Mb PubMed search [3] [4]
Wikidata
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Structure

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

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

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

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