ADAM10 - ADAM metallopeptidase domain 10 | Elisa - Clia - Antibody - Protein

Background

ADAM10, also known as ADAM metallopeptidase domain 10, is a type I transmembrane glycoprotein belonging to the ADAM (a disintegrin and metalloproteinase) family of proteins. It is encoded by the ADAM10 gene located on human chromosome 15. ADAM10 plays crucial roles in various biological processes, including cell adhesion, cell fusion, cell signaling, proteolysis, and ectodomain shedding of membrane proteins. It is involved in the cleavage of a wide range of cell surface proteins, including cytokines, growth factors, adhesion molecules, and receptors. ( Notch receptors, amyloid precursor protein (APP), cadherins, and several cytokines and growth factors). The proteolytic activity of ADAM10 is tightly regulated, as its dysregulation can have significant implications in various diseases, including cancer, Alzheimer's disease, inflammation, and cardiovascular diseases. ADAM10-mediated cleavage of Notch receptors is crucial for various developmental processes, and dysregulation of this process has been implicated in cancer and neurodegenerative diseases. ADAM10 has gained significant attention as a potential therapeutic target for various diseases due to its involvement in critical cellular processes and its ability to modulate the activity of numerous substrates. Inhibition or modulation of ADAM10 activity is being explored as a strategy for the treatment of diseases such as cancer, Alzheimer's disease, and inflammatory disorders. Additionally, ADAM10 inhibitors are being investigated for their potential to block viral entry, including for viruses such as HIV and SARS-CoV-2.

Protein Structure

ADAM10 has a complex multi-domain structure, typical of the ADAM family:

• Signal Peptide: Directs the protein to the secretory pathway.
• Prodomain: Involved in the folding and inhibition of the protease activity until the protein is properly localized.
• Metalloprotease Domain: Contains the catalytic site with a zinc-binding motif critical for proteolytic activity.
• Disintegrin Domain: Facilitates interactions with integrins and other cell surface proteins, playing a key role in cell adhesion.
• Cysteine-Rich Domain: Important for protein stability and interactions.
• EGF-Like Domain: Contributes to 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

ADAM10 is part of the ADAM family, which includes numerous members classified based on their structural domains and functional similarities. ADAM10 is specifically classified under metallopeptidases due to its proteolytic activity.

Function and Biological Significance

ADAM10 performs several critical functions:

1. Proteolysis: The metalloprotease domain is responsible for the shedding of various membrane-bound proteins, including Notch, amyloid precursor protein (APP), and E-cadherin.
2. Notch Signaling: ADAM10 is a key regulator of the Notch signaling pathway, which is crucial for cell differentiation, proliferation, and apoptosis.
3. Cell Adhesion: The disintegrin domain interacts with integrins and other cell surface molecules, influencing cell-cell and cell-matrix adhesion.
4. Cell Migration and Tissue Remodeling: By modulating the extracellular environment and cell adhesion properties, ADAM10 plays a role in cell migration and tissue remodeling.

Interactions

ADAM10 interacts with a variety of proteins and cellular components:

1. Substrate Proteins: Cleaves a wide range of substrates, including Notch, APP, E-cadherin, and various cytokines.
2. Integrins: The disintegrin domain mediates interactions with integrins, affecting cell adhesion and migration.
3. Tetraspanins: Interacts with tetraspanins such as Tspan15, which modulate its activity and substrate specificity.
4. Regulatory Proteins: Interacts with proteins that regulate its trafficking, activation, and proteolytic activity.

Clinical Significance

The function and regulation of ADAM10 have significant implications in various diseases and conditions:

1. Alzheimer's Disease: ADAM10 is involved in the non-amyloidogenic processing of APP, reducing the formation of amyloid-beta peptides implicated in Alzheimer's disease.
2. Cancer: Dysregulated ADAM10 activity can contribute to cancer progression through effects on cell adhesion, migration, and signaling.
3. Autoimmune Diseases: ADAM10-mediated shedding of cytokines and their receptors can influence inflammatory responses and immune regulation.
4. Cardiovascular Diseases: ADAM10 activity affects the shedding of various proteins involved in cardiovascular homeostasis, impacting disease progression.

Summary

ADAM10, a member of the ADAM family, is integral to processes such as proteolysis, cell adhesion, and signaling. It has a multi-domain structure, including a metalloprotease domain for proteolytic activity and a disintegrin domain for cell adhesion. ADAM10 interacts with substrate proteins, integrins, tetraspanins, and regulatory proteins. Clinically, ADAM10 is significant in the context of Alzheimer's disease, cancer, autoimmune diseases, and cardiovascular diseases. Understanding its structure, function, interactions, and clinical implications provides valuable insights into its role in cellular processes and potential as a therapeutic target