Disintegrin and metalloproteinase domain-containing protein 17
Also known as: ADAM17, CSVP, TACE
Function
Transmembrane metalloprotease which mediates the ectodomain shedding of a myriad of transmembrane proteins including adhesion proteins, growth factor precursors and cytokines important for inflammation and immunity. Cleaves the membrane-bound precursor of TNF to its mature soluble form. Responsible for the proteolytical release of soluble JAM3 from endothelial cells surface. Responsible for the proteolytic release of several other cell-surface proteins, including p75 TNF-receptor, interleukin 1 receptor type II, p55 TNF-receptor, transforming growth factor-alpha, L-selectin, growth hormone receptor, MUC1 and the amyloid precursor protein. Acts as an activator of Notch pathway by mediating cleavage of Notch, generating the membrane-associated intermediate fragment called Notch extracellular truncation (NEXT). Plays a role in the proteolytic processing of ACE2. Plays a role in hemostasis through shedding of GP1BA, the platelet glycoprotein Ib alpha chain (By similarity). Mediates the proteolytic cleavage of LAG3, leading to release the secreted form of LAG3 (By similarity). Mediates the proteolytic cleavage of IL6R, leading to the release of secreted form of IL6R. Mediates the proteolytic cleavage and shedding of FCGR3A upon NK cell stimulation, a mechanism that allows for increased NK cell motility and detachment from opsonized target cells. Cleaves TREM2, resulting in shedding of the TREM2 ectodomain.
Classification
- Family (Pfam)
- PF16698 ADAM17_MPD, PF00200 Disintegrin, PF13574 Reprolysin_2
- InterPro
- ADAM10_ADAM17, ADAM17_MPD, ADAM_Metalloproteinase, Disintegrin_dom, Disintegrin_dom_sf, MetalloPept_cat_dom_sf, Peptidase_M12B
- Functional cluster
- Immunoglobulin-Domain Cell Adhesion Proteins
Experimental structures · PDB · 31
- 1BKC X-ray 2.00A
- 1ZXC X-ray 2.28A
- 2A8H X-ray 2.30A
- 2DDF X-ray 1.70A
- 2FV5 X-ray 2.10A
- 2FV9 X-ray 2.02A
- 2I47 X-ray 1.90A
- 2M2F NMR
- 2OI0 X-ray 2.00A
- 3B92 X-ray 2.00A
- 3CKI X-ray 2.30A
- 3E8R X-ray 1.90A
- … and 19 more
A predicted model is available from AlphaFold.
Gene Ontology · 64
- GO:0015629 actin cytoskeleton
- GO:0016324 apical plasma membrane
- GO:0009986 cell surface
- GO:0005737 cytoplasm
- GO:0005788 endoplasmic reticulum lumen
- GO:0000139 Golgi membrane
- GO:0016020 membrane
- GO:0045121 membrane raft
- GO:0005886 plasma membrane
- GO:0019955 cytokine binding
- GO:0004175 endopeptidase activity
- GO:0005178 integrin binding
- GO:0005138 interleukin-6 receptor binding
- GO:0046872 metal ion binding
- GO:0070573 metallodipeptidase activity
- GO:0004222 metalloendopeptidase activity
- GO:1902945 metalloendopeptidase activity involved in amyloid precursor protein catabolic process
- GO:0008237 metallopeptidase activity
- GO:0005112 Notch binding
- GO:0030165 PDZ domain binding
- GO:0008233 peptidase activity
- GO:0017124 SH3 domain binding
- GO:0043120 tumor necrosis factor binding
- GO:0042987 amyloid precursor protein catabolic process
- GO:0030183 B cell differentiation
- GO:0007155 cell adhesion
- GO:0033627 cell adhesion mediated by integrin
- GO:0048870 cell motility
- GO:0071403 cellular response to high density lipoprotein particle stimulus
- GO:0071679 commissural neuron axon guidance
- GO:0140447 cytokine precursor processing
- GO:0050830 defense response to Gram-positive bacterium
- GO:0007173 epidermal growth factor receptor signaling pathway
- GO:0002467 germinal center formation
- GO:0006509 membrane protein ectodomain proteolysis
- GO:0120163 negative regulation of cold-induced thermogenesis
- GO:0030512 negative regulation of transforming growth factor beta receptor signaling pathway
- GO:0002446 neutrophil mediated immunity
- GO:0007220 Notch receptor processing
- GO:0007219 Notch signaling pathway
- GO:0043491 phosphatidylinositol 3-kinase/protein kinase B signal transduction
- GO:0043536 positive regulation of blood vessel endothelial cell migration
- GO:0030307 positive regulation of cell growth
- GO:0030335 positive regulation of cell migration
- GO:0008284 positive regulation of cell population proliferation
- GO:0032722 positive regulation of chemokine production
- GO:0045742 positive regulation of epidermal growth factor receptor signaling pathway
- GO:1900087 positive regulation of G1/S transition of mitotic cell cycle
- GO:0002690 positive regulation of leukocyte chemotaxis
- GO:0010820 positive regulation of T cell chemotaxis
- GO:0032760 positive regulation of tumor necrosis factor production
- GO:1903265 positive regulation of tumor necrosis factor-mediated signaling pathway
- GO:1905564 positive regulation of vascular endothelial cell proliferation
- GO:0002532 production of molecular mediator involved in inflammatory response
- GO:0016485 protein processing
- GO:0006508 proteolysis
- GO:0033025 regulation of mast cell apoptotic process
- GO:0001666 response to hypoxia
- GO:0032496 response to lipopolysaccharide
- GO:0009410 response to xenobiotic stimulus
- GO:0023061 signal release
- GO:0048536 spleen development
- GO:0033077 T cell differentiation in thymus
- GO:0035313 wound healing, spreading of epidermal cells
Disease associations
- inflammatory skin and bowel disease, neonatal, 1 MONDO:0013693
Drugs targeting this protein · 1
- APRATASTAT inhibitor
Related proteins · sequence + function similarity
- Disintegrin and metalloproteinase domain-containing protein 17 0.99
- Disintegrin and metalloproteinase domain-containing protein 17 0.99
- Disintegrin and metalloproteinase domain-containing protein 17 0.99
- Disintegrin and metalloproteinase domain-containing protein 17 homolog 0.87
- Disintegrin and metalloproteinase domain-containing protein 10 0.87
- Disintegrin and metalloproteinase domain-containing protein 10 0.87
- Disintegrin and metalloproteinase domain-containing protein 10 0.87
- Disintegrin and metalloproteinase domain-containing protein 10 0.87
- Disintegrin and metalloproteinase domain-containing protein 10 0.87
- Disintegrin and metalloproteinase domain-containing protein 10 0.87
- ADAM 17-like protease 0.86
- A disintegrin and metalloproteinase with thrombospondin motifs like 0.81
Co-cited proteins · studied together in the literature
- Tetraspanin-8 1 shared papers
- Interleukin-6 receptor subunit alpha 2 shared papers
- FERM domain-containing protein 8 2 shared papers
- Inactive rhomboid protein 2 2 shared papers
- Tumor necrosis factor 1 shared papers
- Triggering receptor expressed on myeloid cells 2 1 shared papers
- FERM domain-containing protein 8 2 shared papers
- Mucin-1 1 shared papers
- Low affinity immunoglobulin gamma Fc region receptor III-A 1 shared papers
- Polypeptide N-acetylgalactosaminyltransferase 11 1 shared papers
- Neurogenic locus notch homolog protein 1 1 shared papers
- Inactive rhomboid protein 1 2 shared papers
Literature · 25 cited papers
- Tetraspanin 8 Subfamily Members Regulate Substrate-Specificity of a Disintegrin and Metalloprotease 17. Cells · 2022
- FRMD8 promotes inflammatory and growth factor signalling by stabilising the iRhom/ADAM17 sheddase complex. Elife · 2018
- iTAP, a novel iRhom interactor, controls TNF secretion by policing the stability of iRhom/TACE. Elife · 2018
- ADAM17 is the main sheddase for the generation of human triggering receptor expressed in myeloid cells (hTREM2) ectodomain and cleaves TREM2 after Histidine 157. Neurosci. Lett. · 2017
- Proteolytic Origin of the Soluble Human IL-6R In Vivo and a Decisive Role of N-Glycosylation. PLoS Biol. · 2017
- Proteolytic Cleavage Governs Interleukin-11 Trans-signaling. Cell Rep. · 2016
- ADAM17-mediated shedding of FcgammaRIIIA on human NK cells: identification of the cleavage site and relationship with activation. J. Immunol. · 2014
- An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J. Proteomics · 2014
- TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein. J. Virol. · 2014
- The heterotaxy gene GALNT11 glycosylates Notch to orchestrate cilia type and laterality. Nature · 2013
- Toward a comprehensive characterization of a human cancer cell phosphoproteome. J. Proteome Res. · 2013
- Inflammatory skin and bowel disease linked to ADAM17 deletion. N. Engl. J. Med. · 2011
- … and 13 more in the literature graph