ADAMTS12 - ADAM metallopeptidase with thrombospondin type 1 motif 12 | Elisa - Clia - Antibody - Protein

Background

ADAMTS12 (ADAM metallopeptidase with thrombospondin type 1 motif 12) is a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family. ADAMTS12 contains several domains typical of the ADAMTS family, including a signal peptide, a propeptide region, a metalloproteinase domain, a disintegrin-like domain, and multiple thrombospondin type 1 (TSP1) motifs. ADAMTS12 is expressed in various tissues during development and in adulthood. It is found in tissues such as the heart, lungs, kidneys, and skeletal tissues. ADAMTS12 plays a significant role in ECM remodeling by cleaving ECM proteins such as aggrecan, versican, and brevican ADAMTS12 is implicated in various aspects of tissue development, particularly in skeletal development. It is involved in processes such as chondrogenesis and osteogenesis , where it regulates ECM composition and structure. ADAMTS12 has been associated with inflammation and immune responses. It can regulate the activity of cytokines, chemokines, and growth factors, influencing immune cell recruitment, activation, and function. ADAMTS12 expression or activity may contribute to inflammatory disorders. ADAMTS12 expression levels have been found to be dysregulated in various cancers, including breast cancer, ovarian cancer, and colorectal cancer. Its roles in ECM remodeling and tissue development suggest potential contributions to tumor progression, invasion, and metastasis.Dysregulation of ADAMTS12 activity has been associated with musculoskeletal disorders such as osteoarthritis and intervertebral disc degeneration. In these conditions, ADAMTS12 contributes to the degradation of ECM components within cartilage and intervertebral discs, leading to tissue degeneration and joint dysfunction. ADAMTS12 expression levels correlate with cancer progression and poor prognosis in several types of cancer. It promotes tumor growth, invasion, and metastasis by facilitating ECM remodeling and inflammation within the tumor microenvironment.

Protein Structure

ADAMTS12, like other ADAMTS family members, has a multi-domain structure:

• Signal Peptide: Directs the nascent protein to the secretory pathway.
• Prodomain: Maintains the enzyme in an inactive form until it is cleaved to activate the enzyme.
• Metalloprotease Domain: Contains the catalytic site with a zinc-binding motif essential for its proteolytic activity.
• Disintegrin-Like Domain: Facilitates interactions with integrins and other cell surface receptors.
• Thrombospondin Type 1 Repeats (TSP1): Involved in binding to ECM components and other proteins, playing roles in cell adhesion and signaling.
• Cysteine-Rich Domain: Contributes to the protein’s stability and interactions.
• Spacer Domain: Connects other domains and influences substrate specificity and binding.
• Additional TSP1 Repeats: ADAMTS12 has multiple TSP1 repeats that enhance interactions with the ECM and other proteins.

Classification and Subtypes

ADAMTS12 is part of the ADAMTS family, which includes several members characterized by the presence of TSP1 motifs and metalloprotease domains. There are no known subtypes of ADAMTS12, but it shares structural and functional similarities with other ADAMTS proteins.

Function and Biological Significance

ADAMTS12 is involved in several critical biological functions:

1. Proteolysis: The metalloprotease domain cleaves specific substrates within the ECM, including aggrecan and versican, playing a role in ECM remodeling.
2. Development: Essential for proper tissue development, including skeletal development and angiogenesis.
3. Inflammation: Modulates inflammatory responses by processing cytokines and chemokines, influencing immune cell recruitment and activity.
4. Cell Migration and Invasion: Affects cell adhesion and motility by interacting with integrins and ECM components.
5. Tissue Remodeling: Involved in restructuring tissues during development, wound healing, and pathological conditions such as fibrosis.

Interactions

ADAMTS12 interacts with various proteins and cellular components:

1. Extracellular Matrix Proteins: Cleaves proteoglycans such as aggrecan and versican, contributing to ECM remodeling.
2. Integrins: The disintegrin-like domain facilitates interactions with integrins, affecting cell adhesion and signaling.
3. Growth Factors and Cytokines: Modulates the activity of growth factors and cytokines by processing them or their binding proteins, influencing cell behavior and tissue development.
4. Thrombospondins: The TSP1 motifs mediate interactions with thrombospondins and other matrix proteins, influencing cell-matrix communication.

Clinical Significance

ADAMTS12 has significant implications in several clinical contexts:

1. Cancer: Overexpression of ADAMTS12 has been associated with tumor progression and metastasis in various cancers, including colorectal, breast, and gastric cancers. It can influence the tumor microenvironment by remodeling the ECM and modulating angiogenesis.
2. Arthritis: Contributes to the degradation of cartilage in osteoarthritis and rheumatoid arthritis by cleaving aggrecan and other matrix components.
3. Fibrosis: Plays a role in fibrotic diseases by regulating tissue remodeling and ECM deposition.
4. Inflammatory Diseases: Altered expression of ADAMTS12 has been linked to inflammatory diseases such as inflammatory bowel disease (IBD) and asthma, where it influences inflammatory responses and tissue remodeling.
5. Cardiovascular Diseases: Implicated in cardiovascular pathologies due to its roles in ECM remodeling and interaction with vascular components.

Summary

ADAMTS12, a member of the ADAMTS family, is crucial for ECM remodeling, tissue development, and inflammation. It has a complex multi-domain structure, including a metalloprotease domain, disintegrin-like domain, and multiple TSP1 motifs. ADAMTS12 interacts with ECM proteins, integrins, growth factors, and thrombospondins, playing essential roles in cell migration, tissue remodeling, and various diseases. Clinically, ADAMTS12 is significant in cancer, arthritis, fibrosis, inflammatory diseases, and cardiovascular diseases. Understanding its structure, functions, interactions, and clinical implications provides valuable insights into its roles in various physiological and pathological processes.