What is ADAMTS7 and where is its gene located in the human genome?

ADAMTS7, which stands for A disintegrin and metalloproteinase with thrombospondin motifs 7, is an enzyme in humans encoded by the ADAMTS7 gene. This gene is located on chromosome 15, specifically at the band 15q24.2.

What are the primary functions of the ADAMTS7 enzyme?

The ADAMTS7 enzyme is primarily responsible for catalyzing the degradation of two key proteins: cartilage oligomeric matrix protein (COMP) and TIMP1 (Tissue Inhibitor of Metalloproteinases 1). This enzymatic activity is crucial in various biological processes.

In which human tissues and cell types is ADAMTS7 expressed?

ADAMTS7 exhibits ubiquitous expression, meaning it is found in many different tissues and cell types throughout the human body. This widespread presence suggests a broad range of physiological roles.

What diseases or conditions have been associated with ADAMTS7?

ADAMTS7 has been linked to several significant health conditions, including cancer across multiple tissue types, arthritis, and an increased risk of coronary artery disease. Its involvement spans various pathological processes.

How many exons does the ADAMTS7 gene contain?

The gene for ADAMTS7 is composed of 25 exons. Exons are the segments of a gene that are transcribed into messenger RNA and ultimately translated into protein.

Describe the overall structure of the ADAMTS7 protein.

The ADAMTS7 protein is a large molecule, consisting of 1686 amino acids. It belongs to the ADAMTS family of proteins and features a characteristic proteinase domain and an ancillary domain, which can vary among different ADAMTS members.

What are the sub-domains within the proteinase domain of ADAMTS7?

The proteinase domain of ADAMTS7 includes a signal peptide, a prodomain, a metalloproteinase domain, and a disintegrin-like domain. These sub-domains work together to enable the enzyme's catalytic activity and interaction with other molecules.

What specific feature is present in the metalloproteinase domain of ADAMTS7 that is crucial for its function?

The metalloproteinase domain of ADAMTS7 contains a cysteine-switch motif within its binding site. This motif is essential for binding the catalytic zinc ion (Zn2+), which is required for the enzyme's proteolytic activity.

What is a proposed pharmacophore model for the metalloproteinase domain of ADAMTS7?

A pharmacophore model for the metalloproteinase domain of ADAMTS7 suggests it has four hydrogen bond donor sites and three hydrogen bond acceptor sites. This model helps in understanding how the enzyme might interact with potential inhibitors or substrates.

How does the ancillary domain of ADAMTS7 differ from its proteinase domain, and what does it contain?

Unlike the conserved proteinase domain, the ancillary domain of ADAMTS proteins varies significantly. In ADAMTS7, this domain contains eight thrombospondin (TSP) type 1 motifs, along with a spacer domain and other specific domains. These TSP motifs are known to be involved in protein-protein interactions and binding to the extracellular matrix.

What role do the TSP type 1 motifs and spacer domain play in ADAMTS7?

The eight TSP type 1 motifs and the spacer domain within ADAMTS7's ancillary domain are crucial for its tight interaction with the extracellular matrix. This interaction helps anchor the enzyme in its functional environment.

How was ADAMTS7 initially identified?

ADAMTS7 was first identified through a yeast two-hybrid screen. The bait used in this screen was the epidermal growth factor (EGF) domain of COMP (cartilage oligomeric matrix protein).

How does ADAMTS7 utilize zinc ions in its function?

As a metalloproteinase, ADAMTS7 requires zinc ions (Zn2+) to catalyze its proteolytic function. Specifically, it uses Zn2+ to break down COMP, its substrate.

What is the role of ADAMTS7 in vascular smooth muscle cells (VSMCs)?

In vascular smooth muscle cells, ADAMTS7 plays a key role in mediating cell migration. This migration is an essential process in the development of conditions like atherosclerosis and restenosis, which involve the narrowing of blood vessels.

What were the findings regarding Adamts7 deficiency in mouse models of atherosclerosis?

In hyperlipidemic mouse models (Ldlr-/- and Apoe-/-), the absence of Adamts7 significantly reduced the formation of atherosclerotic lesions. This suggests that Adamts7 promotes the development of atherosclerosis in these models.

How does Adamts7 deficiency affect neointima formation in mice?

Experiments involving wire-induced injury in Adamts7-deficient mice showed a marked reduction in neointima formation. Neointima is the proliferation of smooth muscle cells within the lumen of a blood vessel after injury, a process implicated in restenosis.

What is the potential therapeutic implication of ADAMTS7's association with atherosclerosis?

Given ADAMTS7's role in promoting atherosclerosis, its inhibition is suggested to be atheroprotective in humans. This implies that developing drugs to block ADAMTS7 activity could be a strategy to prevent or treat coronary artery disease.

How does ADAMTS7 relate to microRNAs (miRNAs) in normal versus disease tissues?

In normal tissues, a negative correlation is observed between the expression levels of certain miRNAs and ADAMTS7. However, this correlation is altered or absent in disease tissues, suggesting that miRNA-target interactions involving ADAMTS7 are disrupted during disease progression.

Could ADAMTS7 and related miRNAs serve as diagnostic tools?

Yes, the expression profiles of specific miRNAs and ADAMTS7 may function as useful diagnostic tools. They could potentially help differentiate between normal tissues and those affected by diseases like cancer and lichen planus.

What is notable about the mutation profile of ADAMTS7 in relation to ethnicity?

ADAMTS7 has been identified as a putative oncogene, and it has been reported that its mutations occur exclusively in individuals of Asian descent. This finding may have specific implications for cancer prevention and treatment strategies in this population.

What is the significance of ADAMTS7 in the pathogenesis of arthritis?

ADAMTS7 plays a crucial role in the development and progression of arthritis. Its involvement highlights it as a potential target for therapeutic interventions aimed at managing joint inflammation and degradation.

Describe the specific axis involving ADAMTS7 in osteoarthritis (OA) pathogenesis.

In the pathogenesis of osteoarthritis, a specific molecular axis has been identified that involves FGF2 (Fibroblast Growth Factor 2), p65 (a subunit of NF-κB), miR-105 (a microRNA), Runx2 (a transcription factor), and ADAMTS7. This complex interplay contributes to the disease process.

How does ADAMTS7 interact with tumor necrosis factor-alpha (TNF-α) in osteoarthritis?

ADAMTS7 forms a positive feedback loop with TNF-α in the pathogenesis of osteoarthritis. This means that ADAMTS7 can stimulate the production or activity of TNF-α, which in turn may further promote the production or activity of ADAMTS7, exacerbating the inflammatory cycle in OA.

What role has ADAMTS7 played in genome-wide association studies (GWAS)?

Genome-wide association studies have identified ADAMTS7 as a genetic locus associated with an increased risk of coronary artery disease. This discovery positions ADAMTS7 as a significant factor in the genetic predisposition to heart disease.

Why is the classification of ADAMTS7 binding sites considered important?

Classifying the binding sites of ADAMTS7 is considered an important step toward developing new therapeutic targets. Understanding precisely where and how ADAMTS7 binds to its substrates or other molecules could lead to the design of drugs that specifically inhibit its activity, potentially treating conditions like coronary artery disease.

Has ADAMTS7 been associated with coronary artery calcification in specific populations?

Yes, significant associations have been found between single nucleotide polymorphisms (SNPs) in the ADAMTS7 gene and coronary artery calcification, particularly in Hispanic populations. This suggests a role for ADAMTS7 in the process of arterial calcification.

What is the significance of ADAMTS7 in multi-locus genetic risk scores for coronary artery disease?

ADAMTS7 is one of 27 genetic loci included in multi-locus genetic risk scores designed to identify individuals at higher risk for coronary artery disease events. These scores combine the effects of multiple genes to provide a more comprehensive assessment of genetic predisposition.

Which specific studies were mentioned in relation to the genetic risk score involving ADAMTS7?

The studies mentioned in relation to the multi-locus genetic risk score involving ADAMTS7 include the Malmö Diet and Cancer study (a community cohort study) and four randomized controlled trials: JUPITER and ASCOT (primary prevention cohorts), and CARE and PROVE IT-TIMI 22 (secondary prevention cohorts).

What is the overall implication of ADAMTS7's involvement in cardiovascular disease?

The association of ADAMTS7 with coronary artery disease, coronary artery calcification, and its inclusion in genetic risk scores indicates its significant role in cardiovascular health. Targeting ADAMTS7 could potentially offer new therapeutic avenues for preventing or managing these conditions.

How does the structure of ADAMTS7 facilitate its interaction with the extracellular matrix?

ADAMTS7 interacts tightly with the extracellular matrix due to the presence of eight thrombospondin (TSP) type 1 motifs and a spacer domain within its ancillary domain. These structural components are key to anchoring the protein within the tissue environment where it performs its functions.

What is the relationship between ADAMTS7 and hepatocellular carcinoma (HCC)?

ADAMTS7 has been identified as a potential oncogene, and its mutations are found exclusively in individuals of Asian descent. This suggests that ADAMTS7 may play a role in the development of hepatocellular carcinoma, particularly in Asian populations, and could be relevant for targeted therapies.

What is the function of TIMP1 in relation to ADAMTS7?

ADAMTS7 catalyzes the degradation of TIMP1 (Tissue Inhibitor of Metalloproteinases 1). TIMP1 normally acts to inhibit matrix metalloproteinases, so ADAMTS7's action on TIMP1 could indirectly affect the balance of extracellular matrix remodeling.

Adamts7 Wiki: ADAMTS7: The Molecular Sculptor of Health and Disease

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Molecular Architecture

The Gene

The gene encoding the ADAMTS7 protein, ADAMTS7, is located on human chromosome 15, specifically within the 15q24.2 band. This gene comprises 25 exons, which are the segments of DNA that code for proteins.^[1]

The Protein

ADAMTS7 is a substantial protein, consisting of 1686 amino acids. It belongs to the ADAMTS (A Disintegrin And Metalloproteinase with Thrombospondin Motifs) family, a group of 19 related enzymes in humans. Key structural features include:

Metalloproteinase Domain: This catalytic domain is responsible for the enzyme's enzymatic activity, utilizing a zinc ion (Zn²⁺) for substrate cleavage. It features a critical cysteine-switch motif essential for zinc binding.^[9]
Disintegrin-like Domain: Adjacent to the metalloproteinase domain, this region is characteristic of the ADAMTS family.
Ancillary Domains: These vary among ADAMTS proteins and contribute to substrate interaction and localization. ADAMTS7 is distinguished by eight thrombospondin (TSP) type 1 motifs and a spacer domain, which facilitate its strong interaction with the extracellular matrix.^[8]

A proposed pharmacophore model identifies four hydrogen bond donor sites and three acceptor sites within the metalloproteinase domain, crucial for its molecular interactions.^[8]

Biological Roles

Proteolytic Activity

As a metalloproteinase, ADAMTS7 catalyzes the degradation of specific extracellular matrix components. Its primary identified substrates include:

Cartilage Oligomeric Matrix Protein (COMP): ADAMTS7 directly binds to and degrades COMP, a key component of cartilage.^[3]
TIMP1: It also degrades Tissue Inhibitor of Metalloproteinases 1, suggesting a regulatory role in matrix remodeling.^[4]

Cardiovascular Health

ADAMTS7 plays a significant role in vascular smooth muscle cell (VSMC) migration. This process is critical during the development of atherosclerosis (hardening of the arteries) and restenosis (re-narrowing of arteries after procedures like angioplasty).^[10]

Studies in mouse models have demonstrated that deficiency in Adamts7 markedly attenuates the formation of atherosclerotic lesions. Similarly, wire-injury experiments in Adamts7-deficient mice showed reduced neointima formation.^[11] These findings suggest that inhibiting ADAMTS7 could be a protective strategy against atherosclerosis in humans.^[11]

Clinical Significance

Disease Associations

ADAMTS7 is implicated in several disease states, acting as both a potential marker and a contributor to pathology:

Cancer: It has been identified as a putative oncogene. Notably, mutations in ADAMTS7 have been reported exclusively in Asian populations, suggesting potential implications for the prevention and treatment of hepatocellular carcinoma (liver cancer).^[5] Altered interactions between specific microRNAs (miRNAs) and ADAMTS7 in disease tissues, compared to normal tissues, suggest its potential utility as a diagnostic marker.^[12]
Arthritis: ADAMTS7 is a key player in the pathogenesis of arthritis, particularly osteoarthritis (OA). It forms a positive feedback loop with tumor necrosis factor-alpha (TNF-α) in OA development.^[13]^[14]

Coronary Artery Disease

Genome-wide association studies have identified ADAMTS7 as a significant genetic risk locus for coronary artery disease (CAD).^[7]^[15]

Specific single nucleotide polymorphisms (SNPs) within the ADAMTS7 gene have shown significant associations with coronary artery calcification, even in specific ethnic groups like Hispanics.^[15] Furthermore, a multi-locus genetic risk score incorporating ADAMTS7 and 26 other loci has been developed. This score can identify individuals at increased risk for CAD events and predict enhanced clinical benefit from statin therapy, highlighting ADAMTS7's role in personalized cardiovascular medicine.^[7] Research into classifying ADAMTS7 binding sites is underway, aiming to develop novel therapeutic targets for CAD.^[8]

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ADAMTS7: The Molecular Sculptor

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Molecular Architecture 🏗️

🧬 The Gene

⚛️ The Protein

Biological Roles ⚙️

✂️ Proteolytic Activity

❤️ Cardiovascular Health

Clinical Significance ⚕️

⚠️ Disease Associations

❤️‍🩹 Coronary Artery Disease

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📜 Important Notice

Dive in with Flashcard Learning!

Molecular Architecture

The Gene

The Protein

Biological Roles

Proteolytic Activity

Cardiovascular Health

Clinical Significance

Disease Associations

Coronary Artery Disease

Teacher's Corner

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Gamer's Corner

Discover other topics to study!

References

Feedback & Support

Disclaimer

Important Notice