Wikipedia

ADAM17

A disintegrin and metalloprotease 17 (ADAM17), also called TACE (tumor necrosis factor-α-converting enzyme), is a 70-kDa enzyme that belongs to the ADAM protein family of disintegrins and metalloproteases, activated by substrate presentation.

ADAM17
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesADAM17, ADAM18, CD156B, CSVP, NISBD, NISBD1, TACE, ADAM metallopeptidase domain 17
External IDsOMIM: 603639; MGI: 1096335; HomoloGene: 2395; GeneCards: ADAM17; OMA:ADAM17 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

6868

11491

Ensembl

ENSG00000151694

ENSMUSG00000052593

UniProt

P78536

Q9Z0F8

RefSeq (mRNA)

NM_003183
NM_001382777
NM_001382778
NM_021832

NM_001277266
NM_009615
NM_001291871

RefSeq (protein)

NP_003174

NP_001264195
NP_001278800
NP_033745

Location (UCSC)Chr 2: 9.49 – 9.56 MbChr 12: 21.37 – 21.42 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Structure

edit

ADAM17 is an 824-amino acid polypeptide.[5][6]

ADAM17 has multidomain structure that includes a pro-domain, a metallo-protease domain, a disintegrin domain, a cysteine-rich domain, an EGF-like domain, a transmembrane domain, and a cytoplasmic tail.[7][8][9] The metalloprotease domain is responsible for the enzyme's catalytic activity, cleaving membrane-bound proteins, including cytokines like TNF-alpha, to release their soluble forms. The disintegrin and cysteine-rich domains are implicated in cell adhesion and interaction with integrins, while the transmembrane domain anchors the protein in the membrane. The cytoplasmic tail is involved in intracellular signaling and protein-protein interactions. ADAM17's activity is tightly regulated through multiple mechanisms, including the removal of its pro-domain and interactions with regulatory proteins such as TIMPs (tissue inhibitors of metalloproteinases).[10]

Function

edit

ADAM17 is understood to be involved in the processing of tumor necrosis factor alpha (TNF-α) at the surface of the cell, and from within the intracellular membranes of the trans-Golgi network. This process, which is also known as 'shedding', involves the cleavage and release of a soluble ectodomain from membrane-bound pro-proteins (such as pro-TNF-α), and is of known physiological importance. ADAM17 was the first 'sheddase' to be identified, and is also understood to play a role in the release of a diverse variety of membrane-anchored cytokines, cell adhesion molecules, receptors, ligands, and enzymes.

Cloning of the TNF-α gene revealed it to encode a 26 kDa type II transmembrane pro-polypeptide that becomes inserted into the cell membrane during its maturation. At the cell surface, pro-TNF-α is biologically active, and is able to induce immune responses via juxtacrine intercellular signaling. However, pro-TNF-α can undergo a proteolytic cleavage at its Ala76-Val77 amide bond, which releases a soluble 17kDa extracellular domain (ectodomain) from the pro-TNF-α molecule. This soluble ectodomain is the cytokine commonly known as TNF-α, which is of pivotal importance in paracrine signaling. This proteolytic liberation of soluble TNF-α is catalyzed by ADAM17.

ADAM17 may play a prominent role in the Notch signaling pathway, during the proteolytic release of the Notch intracellular domain (from the Notch1 receptor) that occurs following ligand binding. ADAM17 also regulates the MAP kinase signaling pathway by regulating shedding of the EGFR ligand amphiregulin in the mammary gland.[11] ADAM17 also has a role in the shedding of L-selectin, a cellular adhesion molecule.[12]

Activation

edit

The localization of ADAM17 is speculated to be an important determinant of shedding activity. TNF-α processing has classically been understood to occur in the trans-Golgi network, and be closely connected to transport of soluble TNF-α to the cell surface. Shedding is also associated with clustering of ADAM17 with its substrate, membrane bound TNF, in lipid rafts. [13] The overall process is called substrate presentation and regulated by cholesterol. Research also suggests that the majority of mature, endogenous ADAM17 may be localized to a perinuclear compartment, with only a small amount of TACE being present on the cell surface. The localization of mature ADAM17 to a perinuclear compartment, therefore, raises the possibility that ADAM17-mediated ectodomain shedding may also occur in the intracellular environment, in contrast with the conventional model.

Functional ADAM17 has been documented to be ubiquitously expressed in the human colon, with increased activity in the colonic mucosa of patients with ulcerative colitis, a main form of inflammatory bowel disease. Other experiments have also suggested that expression of ADAM17 may be inhibited by ethanol.[14]

Interactions

edit

ADAM17 has been shown to interact with:

Clinical significance

edit

Adam17 may facilitate entry of the SARS‑CoV‑2 virus, possibly by enabling fusion of virus particles with the cytoplasmic membrane.[20] Adam17 has similar ACE2 cleavage activity as TMPRSS2, but by forming soluble ACE2, Adam17 may actually have the protective effect of blocking circulating SARS‑CoV‑2 virus particles.[20]

Adam17 sheddase activity may contribute to COVID-19 inflammation by cleavage of TNF-α and Interleukin-6 receptor.[20]

Recently, ADAM17 was discovered as a crucial mediator of resistance to radiotherapy. Radiotherapy can induce a dose-dependent increase of furin-mediated cleavage of the ADAM17 proform to active ADAM17, which results in enhanced ADAM17 activity in vitro and in vivo. It was also shown that radiotherapy activates ADAM17 in non-small cell lung cancer, which results in shedding of multiple survival factors, growth factor pathway activation, and radiotherapy-induced treatment resistance.[21]

References

edit
  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000151694 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000052593 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, et al. (February 1997). "A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells". Nature. 385 (6618): 729–733. Bibcode:1997Natur.385..729B. doi:10.1038/385729a0. PMID 9034190. S2CID 4251053.
  6. ^ Moss ML, Jin SL, Milla ME, Bickett DM, Burkhart W, Carter HL, et al. (February 1997). "Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha". Nature. 385 (6618): 733–736. Bibcode:1997Natur.385..733M. doi:10.1038/385733a0. PMID 9034191. S2CID 4335616.
  7. ^ Primakoff P, Myles DG (February 2000). "The ADAM gene family: surface proteins with adhesion and protease activity". Trends in Genetics. 16 (2): 83–87. doi:10.1016/s0168-9525(99)01926-5. PMID 10652535.
  8. ^ Seals DF, Courtneidge SA (January 2003). "The ADAMs family of metalloproteases: multidomain proteins with multiple functions". Genes & Development. 17 (1): 7–30. doi:10.1101/gad.1039703. PMID 12514095.
  9. ^ Blobel CP (January 2005). "ADAMs: key components in EGFR signalling and development". Nature Reviews. Molecular Cell Biology. 6 (1): 32–43. doi:10.1038/nrm1548. PMID 15688065.
  10. ^ Edwards DR, Handsley MM, Pennington CJ (October 2008). "The ADAM metalloproteinases". Molecular Aspects of Medicine. 29 (5): 258–289. doi:10.1016/j.mam.2008.08.001. PMC 7112278. PMID 18762209.
  11. ^ Sternlicht MD, Sunnarborg SW, Kouros-Mehr H, Yu Y, Lee DC, Werb Z (September 2005). "Mammary ductal morphogenesis requires paracrine activation of stromal EGFR via ADAM17-dependent shedding of epithelial amphiregulin". Development. 132 (17): 3923–3933. doi:10.1242/dev.01966. PMC 2771180. PMID 16079154.
  12. ^ Li Y, Brazzell J, Herrera A, Walcheck B (October 2006). "ADAM17 deficiency by mature neutrophils has differential effects on L-selectin shedding". Blood. 108 (7): 2275–2279. doi:10.1182/blood-2006-02-005827. PMC 1895557. PMID 16735599.
  13. ^ Tellier E, Canault M, Rebsomen L, Bonardo B, Juhan-Vague I, Nalbone G, et al. (December 2006). "The shedding activity of ADAM17 is sequestered in lipid rafts". Experimental Cell Research. 312 (20): 3969–3980. doi:10.1016/j.yexcr.2006.08.027. PMID 17010968.
  14. ^ Taïeb J, Delarche C, Ethuin F, Selloum S, Poynard T, Gougerot-Pocidalo MA, et al. (December 2002). "Ethanol-induced inhibition of cytokine release and protein degranulation in human neutrophils". Journal of Leukocyte Biology. 72 (6): 1142–1147. doi:10.1189/jlb.72.6.1142. PMID 12488495. S2CID 9712196.
  15. ^ Peiretti F, Deprez-Beauclair P, Bonardo B, Aubert H, Juhan-Vague I, Nalbone G (May 2003). "Identification of SAP97 as an intracellular binding partner of TACE". Journal of Cell Science. 116 (Pt 10): 1949–1957. doi:10.1242/jcs.00415. PMID 12668732.
  16. ^ Nelson KK, Schlöndorff J, Blobel CP (November 1999). "Evidence for an interaction of the metalloprotease-disintegrin tumour necrosis factor alpha convertase (TACE) with mitotic arrest deficient 2 (MAD2), and of the metalloprotease-disintegrin MDC9 with a novel MAD2-related protein, MAD2beta". The Biochemical Journal. 343 Pt 3 (Pt 3): 673–680. doi:10.1042/0264-6021:3430673. PMC 1220601. PMID 10527948.
  17. ^ Poghosyan Z, Robbins SM, Houslay MD, Webster A, Murphy G, Edwards DR (February 2002). "Phosphorylation-dependent interactions between ADAM15 cytoplasmic domain and Src family protein-tyrosine kinases". The Journal of Biological Chemistry. 277 (7): 4999–5007. doi:10.1074/jbc.M107430200. PMID 11741929.
  18. ^ Díaz-Rodríguez E, Montero JC, Esparís-Ogando A, Yuste L, Pandiella A (June 2002). "Extracellular signal-regulated kinase phosphorylates tumor necrosis factor alpha-converting enzyme at threonine 735: a potential role in regulated shedding". Molecular Biology of the Cell. 13 (6): 2031–2044. doi:10.1091/mbc.01-11-0561. PMC 117622. PMID 12058067.
  19. ^ Grieve A, Xu H, Künzel U, Bambrough P, Sieber B, Freeman M (April 2017). "Phosphorylation of iRhom2 at the plasma membrane controls mammalian TACE-dependent inflammatory and growth factor signalling". eLife. 6. doi:10.7554/eLife.23968. PMC 5436907. PMID 28432785.
  20. ^ a b c Zipeto D, Palmeira JD, Argañaraz GA, Argañaraz ER (2020). "ACE2/ADAM17/TMPRSS2 Interplay May Be the Main Risk Factor for COVID-19". Frontiers in Immunology. 11: 576745. doi:10.3389/fimmu.2020.576745. PMC 7575774. PMID 33117379.
  21. ^ Sharma A, Bender S, Zimmermann M, Riesterer O, Broggini-Tenzer A, Pruschy MN (September 2016). "Secretome Signature Identifies ADAM17 as Novel Target for Radiosensitization of Non-Small Cell Lung Cancer". Clinical Cancer Research. 22 (17): 4428–4439. doi:10.1158/1078-0432.CCR-15-2449. PMID 27076628.

Further reading

edit
edit
Retrieved from "https://en.wikipedia.org/w/index.php?title=ADAM17&oldid=1255524546"