Adam17 Protein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
Overview
ADAM17 (A Disintegrin And Metalloproteinase 17), also known as TACE (TNF-α Converting Enzyme), is a transmembrane metalloproteinase that functions as a major sheddase, releasing the extracellular domains of numerous membrane-bound proteins. It is a critical therapeutic target in cancer, inflammatory diseases, and Alzheimer's disease. [@hu2005]
Protein Information
Structure
ADAM17 is a type I transmembrane protein composed of multiple functional domains:
Signal Peptide: Directs protein to the secretory pathway
Prodomain: N-terminal propeptide that maintains zymogen inactivity (approximately 20 kDa)
Metalloproteinase Domain: Catalytic domain containing the zinc-binding consensus sequence HEXGHNLG (residues 405-412), essential for proteolytic activity
Disintegrin Domain: Mediates substrate recognition and cell adhesion interactions
Transmembrane Domain: Single pass α-helical membrane anchor
Cytoplasmic Tail: Contains multiple serine and threonine phosphorylation sites, regulates intracellular trafficking and activity
The three-dimensional structure reveals a deep substrate-binding cleft in the metalloproteinase domain, explaining its broad substrate specificity.
Normal Function
ADAM17 is one of the most important sheddases in the human proteome, with over 80 known substrates:
Inflammatory Signaling
TNF-α Processing: ADAM17 is the primary enzyme responsible for cleaving membrane-bound pro-TNF-α to generate soluble, bioactive TNF-α, a key proinflammatory cytokine in the immune response
TGF-α Release: Generates soluble transforming growth factor alpha, an EGFR ligand involved in cell proliferation
Amphiregulin (AR): Produces the EGF receptor ligand amphiregulin, important for tissue repair
HB-EGF: Processes heparin-binding EGF-like growth factor, involved in cardiac development and repair
Notch Signaling
Notch Receptor Cleavage: Essential for Notch receptor activation through constitutive shedding, enabling [γ-secretase](/entities/gamma-secretase)-mediated intramembrane cleavage
Neuronal Function
APP Processing: Acts as α-secretase in the amyloid precursor protein (APP) processing pathway, generating soluble APPα (sAPPα) and precluding amyloid-β generation
Synaptic Plasticity: Regulates [NMDA](/entities/nmda-receptor) receptor subunit availability and synaptic protein function
Role in Disease
Alzheimer's Disease
ADAM17 plays a complex and multifaceted role in Alzheimer's disease pathogenesis:
[Amyloid Precursor Protein](/entities/app-protein) Processing: As an α-secretase, ADAM17 competes directly with [β-secretase](/entities/bace1) (BACE1) for APP processing. Enhanced ADAM17 activity shifts APP processing toward the non-amyloidogenic pathway, reducing amyloid-β production
Neuroinflammation: Regulates TNF-α and IL-6R shedding, modulating neuroinflammatory responses in the AD brain
Neuronal Survival: sAPPα generated by ADAM17 has neuroprotective properties, promoting neuronal survival and synaptic plasticity
Therapeutic Potential: Small molecule ADAM17 activators represent a potential therapeutic approach for AD, though achieving tissue-specific activation remains challenging
Cancer
Oncogenic Shedding: Overexpression in multiple cancers (breast, ovarian, pancreatic, lung) promotes tumor progression through growth factor release
Metastasis: Facilitates epithelial-mesenchymal transition and invasion through substrate release
Drug Resistance: Contributes to resistance to targeted therapies
Inflammatory Diseases
Rheumatoid Arthritis: Central to TNF-α-mediated joint inflammation; ADAM17 inhibitors have been tested clinically
Inflammatory Bowel Disease: Regulates mucosal inflammation through cytokine and growth factor shedding
Psoriasis: Mediates keratinocyte hyperproliferation via growth factor release
Therapeutic Targeting
Challenges in Drug Development
Broad Substrate Specificity: Global inhibition affects multiple physiological pathways
Tissue-selective targeting needed
2. Compensatory Mechanisms: Other sheddases can partially compensate
Side Effects: TNF-α inhibition increases infection risk
Research Directions
ADAM17 Activators: Developing small molecules that selectively increase ADAM17 activity toward APP without affecting inflammatory substrates
Substrate-Selective Inhibitors: Engineering inhibitors that block specific substrate shedding while preserving others
Biomarkers: Soluble ADAM17 ectodomain as a biomarker for disease progression
Key Publications
ADAMs family members as amyloid precursor protein alpha-secretases - Allinson et al. J Neurosci Res. 2003;74(3):342-352. PMID: 14598297(https://pubmed.ncbi.nlm.nih.gov/14598297/)
Structure of the ADAM17 catalytic domain and insight into inhibition - Hu et al. Biochem J. 2005;387(Pt 1):17-28. PMID: 15584739(https://pubmed.ncbi.nlm.nih.gov/15584739/)
TACE/ADAM17 is required for Notch activation in vivo - Krebs et al. J Cell Biol. 2003;163(5):1133. PMID: 14657234(https://pubmed.ncbi.nlm.nih.gov/14657234/)
ADAM17 as a therapeutic target in cancer and inflammatory diseases - Dreymueller et al. Nat Rev Drug Discov. 2015;14(11):735-746. PMID: 26338155(https://pubmed.ncbi.nlm.nih.gov/26338155/)
Regulation of ADAM17 activity and function - Gooz et al. Cell Signal. 2016;28(11):1685-1700. PMID: 27498086(https://pubmed.ncbi.nlm.nih.gov/27498086/)
ADAM17 and Alzheimer's disease - post-translational modification of APP processing** - Howcroft et al. J Neurochem. 2013;126(4):461-467. PMID: 23682896(https://pubmed.ncbi.nlm.nih.gov/23682896/)
TNF-alpha converting enzyme: a sheddase with therapeutic potential - Black et al. Trends Pharmacol Sci. 2003;24(10):524-528. PMID: 14559409(https://pubmed.ncbi.nlm.nih.gov/14559409/)
ADAM17 in cancer metastasis - McGowan et al. Clin Cancer Res. 2014;20(1):35-43. PMID: 24189364(https://pubmed.ncbi.nlm.nih.gov/24189364/)
The study of Adam17 Protein has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
References
[Allinson TM, et al, (2003) ADAMs family members as amyloid precursor protein alpha-secretases (2003)](https://pubmed.ncbi.nlm.nih.gov/14598297/)
[Hu J, et al, (2005) Structure of the ADAM17 catalytic domain and insight into inhibition (2005)](https://pubmed.ncbi.nlm.nih.gov/15584739/)
[Krebs LT, et al, (2003) TACE/ADAM17 is required for Notch activation in vivo (2003)](https://pubmed.ncbi.nlm.nih.gov/14657234/)
[Dreymueller D, et al, (2015) ADAM17 as a therapeutic target in cancer and inflammatory diseases (2015)](https://pubmed.ncbi.nlm.nih.gov/26338155/)
[Gooz M, et al, (2016) Regulation of ADAM17 activity and function (2016)](https://pubmed.ncbi.nlm.nih.gov/27498086/)
[Howcroft TK, et al, (2013) ADAM17 in Alzheimer's disease (2013)](https://pubmed.ncbi.nlm.nih.gov/23682896/)
[Black RA, et al, (2003) TNF-alpha converting enzyme: a sheddase with therapeutic potential (2003)](https://pubmed.ncbi.nlm.nih.gov/14559409/)
[McGowan PM, et al, (2014) ADAM17 in cancer metastasis (2014)](https://pubmed.ncbi.nlm.nih.gov/24189364/)