ADAM17 - ADAM metallopeptidase domain 17| Elisa - Clia - Antibody - Protein

Background

ADAM17, also known as ADAM metallopeptidase domain 17 or tumor necrosis factor-alpha converting enzyme (TACE), is a member of the ADAM family of proteins. Like other ADAM proteins, it possesses a complex domain structure with distinct functional regions, including a metalloproteinase domain responsible for its proteolytic activity.ADAM17 is a transmembrane protein. Consists of several domains, including a metalloproteinase domain, a disintegrin domain, a cysteine-rich domain, an EGF-like domain, a transmembrane domain, and a cytoplasmic tail. Is responsible for the cleavage and release of various membrane-bound proteins, including cytokines, growth factors, receptors, and adhesion molecules. One of its most well-known substrates is tumor necrosis factor-alpha (TNF-α).ADAM17 cleaves the membrane-bound precursor form of TNF-α to release its soluble form into the extracellular space. Soluble TNF-α can then bind to its receptors on target cells, initiating signaling cascades involved in inflammation, apoptosis, and immune responses.ADAM17 also sheds and regulates the activity of other important proteins, including epidermal growth factor receptor (EGFR) ligands, transforming growth factor-alpha (TGF-α), and Notch receptor. Dysregulation of ADAM17 activity has been implicated in various diseases, including inflammatory disorders, autoimmune diseases, cancer, and cardiovascular diseases. In particular, increased ADAM17 activity and elevated levels of its substrates, such as TNF-α, have been observed in conditions like rheumatoid arthritis, inflammatory bowel disease, and certain cancers. Given its central role in inflammation and disease pathogenesis, ADAM17 is considered a promising therapeutic target

Protein Structure

ADAM17 has a complex multi-domain structure typical of ADAM proteins:

• Signal Peptide: Directs the protein to the secretory pathway.
• Prodomain: Maintains the enzyme in an inactive form until it reaches its proper cellular location and is cleaved off to activate the enzyme.
• Metalloprotease Domain: Contains the catalytic site with a zinc-binding motif essential for its proteolytic function.
• Disintegrin Domain: Facilitates interactions with integrins and other cell surface receptors, contributing to cell adhesion and signaling.
• Cysteine-Rich Domain: Contributes to the protein’s stability and interactions.
• EGF-Like Domain: Participates in protein-protein interactions.
• Transmembrane Domain: Anchors the protein in the cell membrane.
• Cytoplasmic Tail: Involved in intracellular signaling and interactions with cytoskeletal elements.

Classification and Subtypes

ADAM17 belongs to the ADAM family, which includes proteins with both metalloprotease and disintegrin domains. It is specifically classified under metalloproteases due to its catalytic activity in proteolysis.

Function and Biological Significance

ADAM17 performs several critical functions:

1. Proteolysis: The metalloprotease domain is responsible for cleaving the ectodomains of various transmembrane proteins, a process known as "shedding."
2. Cytokine Release: ADAM17 is well-known for its role in releasing the extracellular domain of Tumor Necrosis Factor-α (TNF-α), a key cytokine in inflammation.
3. Growth Factor Activation: Activates several growth factors, including transforming growth factor-alpha (TGF-α) and heparin-binding EGF-like growth factor (HB-EGF), by shedding their membrane-bound precursors.
4. Cell Signaling: Modulates signaling pathways by shedding receptors and ligands, influencing processes like cell proliferation, migration, and apoptosis.
5. Development: Involved in embryonic development and tissue remodeling by regulating the availability of growth factors and cytokines.

Interactions

ADAM17 interacts with various proteins and cellular components:

1. Cytokine Precursors: Cleaves precursors of cytokines such as TNF-α, facilitating their release and activity.
2. Growth Factor Precursors: Activates growth factors by cleaving their membrane-bound precursors.
3. Integrins: The disintegrin domain mediates interactions with integrins, affecting cell adhesion and signaling.
4. Cell Surface Receptors: Shedding of receptors like the IL-6 receptor, TNF receptors, and EGFR ligands, modulating their activity and downstream signaling.

Clinical Significance

The function and regulation of ADAM17 have significant implications in various diseases and conditions:

1. Inflammatory Diseases: ADAM17 is a key mediator in the release of TNF-α and other pro-inflammatory cytokines, playing a critical role in conditions like rheumatoid arthritis and inflammatory bowel disease.
2. Cancer: Dysregulated ADAM17 activity is implicated in cancer progression and metastasis through its role in shedding growth factors and receptors, promoting cell proliferation, migration, and survival.
3. Cardiovascular Diseases: ADAM17 contributes to cardiovascular pathology by modulating inflammatory responses and affecting the shedding of receptors involved in vascular homeostasis.
4. Fibrosis: Involved in tissue remodeling processes that can lead to fibrosis, making it a potential target for antifibrotic therapies.
5. Neurodegenerative Diseases: Altered ADAM17 activity has been linked to neuroinflammation and the progression of diseases like Alzheimer's.

Summary

ADAM17, a member of the ADAM family, is crucial for processes such as proteolysis, cytokine release, growth factor activation, cell signaling, and development. It has a multi-domain structure, including a metalloprotease domain for proteolytic activity and a disintegrin domain for cell adhesion. ADAM17 interacts with cytokine and growth factor precursors, integrins, and cell surface receptors. Clinically, ADAM17 is significant in the context of inflammatory diseases, cancer, cardiovascular diseases, fibrosis, and neurodegenerative diseases. Understanding its structure, function, interactions, and clinical implications provides valuable insights into its role in cellular processes and potential as a therapeutic target.