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Details on Person UniProt:P78536 ADAM17

Class:Id	ReferenceGeneProduct:49678
_chainChangeLog	signal peptide:1-17 added on Fri February 6 2015;propeptide:18-214 added on Fri February 6 2015;chain:215-824 added on Fri February 6 2015
_displayName	UniProt:P78536 ADAM17
_timestamp	2026-02-20 21:56:30
chain	signal peptide:1-17 propeptide:18-214 chain:215-824
checksum	5B1032F6B88A837F
comment	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 (PubMed:24226769, PubMed:24227843, PubMed:28060820, PubMed:28923481). Cleaves the membrane-bound precursor of TNF to its mature soluble form (PubMed:36078095, PubMed:9034191). Responsible for the proteolytical release of soluble JAM3 from endothelial cells surface (PubMed:20592283). 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 (PubMed:12441351). Acts as an activator of Notch pathway by mediating cleavage of Notch, generating the membrane-associated intermediate fragment called Notch extracellular truncation (NEXT) (PubMed:24226769). Plays a role in the proteolytic processing of ACE2 (PubMed:24227843). 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 (PubMed:26876177, PubMed:28060820). 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 (PubMed:28923481).CATALYTIC ACTIVITY Narrow endopeptidase specificity. Cleaves Pro-Leu-Ala-Gln-Ala-\|-Val-Arg-Ser-Ser-Ser in the membrane-bound, 26-kDa form of tumor necrosis factor alpha (TNFalpha). Similarly cleaves other membrane-anchored, cell-surface proteins to 'shed' the extracellular domains.COFACTOR Binds 1 zinc ion per subunit.SUBUNIT Interacts with MAD2L1, MAPK14 and MUC1 (PubMed:12441351, PubMed:20188673). Interacts with iRhom1/RHBDF1 and iRhom2/RHBDF2 (PubMed:29897333). Interacts with FRMD8 via its interaction with iRhom1/RHBDF1 and iRhom2/RHBDF2 (PubMed:29897333). Interacts with TSPAN8 (PubMed:36078095).INTERACTION Ubiquitously expressed. Expressed at highest levels in adult heart, placenta, skeletal muscle, pancreas, spleen, thymus, prostate, testes, ovary and small intestine, and in fetal brain, lung, liver and kidney. Expressed in natural killer cells (at protein level) (PubMed:24337742).INDUCTION In arthritis-affected cartilage.DOMAIN Must be membrane anchored to cleave the different substrates. The cytoplasmic domain is not required for the this activity. Only the catalytic domain is essential to shed TNF and p75 TNFR (By similarity).DOMAIN The conserved cysteine present in the cysteine-switch motif binds the catalytic zinc ion, thus inhibiting the enzyme. The dissociation of the cysteine from the zinc ion upon the activation-peptide release activates the enzyme.PTM The precursor is cleaved by a furin endopeptidase.PTM Phosphorylated. Stimulation by growth factor or phorbol 12-myristate 13-acetate induces phosphorylation of Ser-819 but decreases phosphorylation of Ser-791. Phosphorylation at Thr-735 by MAPK14 is required for ADAM17-mediated ectodomain shedding.DISEASE The disease is caused by variants affecting the gene represented in this entry.ONLINE INFORMATION Tumor necrosis factor alpha-converting enzyme entry
description	recommendedName: Disintegrin and metalloproteinase domain-containing protein 17 shortName: ADAM 17 ecNumber evidence="10 13 16 20"3.4.24.86 alternativeName: Snake venom-like protease alternativeName: TNF-alpha convertase alternativeName: TNF-alpha-converting enzyme cdAntigenNameCD156b/cdAntigenName
geneName	ADAM17 CSVP TACE
identifier	P78536
isSequenceChanged	FALSE
keyword	3D-structure Alternative splicing Cell membrane Cleavage on pair of basic residues Direct protein sequencing Disulfide bond Glycoprotein Hydrolase Membrane Metal-binding Metalloprotease Notch signaling pathway Phosphoprotein Protease Proteomics identification Reference proteome SH3-binding Signal Transmembrane Transmembrane helix Zinc Zymogen
modified	[InstanceEdit:9836292] Weiser, Joel, 2023-05-25 [InstanceEdit:9852000] Weiser, Joel, 2023-11-03 [InstanceEdit:9917590] Weiser, Joel, 2024-08-09 [InstanceEdit:9926675] Weiser, Joel, 2024-11-03 [InstanceEdit:9939033] Weiser, Joel, 2025-02-21 [InstanceEdit:9983091] Weiser, Joel, 2026-02-20
name	ADAM17
referenceDatabase	[ReferenceDatabase:2] UniProt
referenceGene	[ReferenceDNASequence:8999304] ENSEMBL:ENSG00000151694 ADAM17 [Homo sapiens]
secondaryIdentifier	ADA17_HUMAN O60226
sequenceLength	824
species	[Species:48887] Homo sapiens
(isoformParent)	[ReferenceIsoform:143838] UniProt:P78536-2 ADAM17 [Homo sapiens] [ReferenceIsoform:404833] UniProt:P78536-1 ADAM17 [Homo sapiens]
(referenceEntity)	[EntityWithAccessionedSequence:179878] ADAM17 [plasma membrane] [Homo sapiens] [EntityWithAccessionedSequence:9662759] Clone of ADAM17(215-?) [Golgi membrane] [Homo sapiens] [EntityWithAccessionedSequence:9662763] ADAM17 [endoplasmic reticulum lumen] [Homo sapiens] [EntityWithAccessionedSequence:9662784] ADAM17(1-214) [Golgi membrane] [Homo sapiens] [EntityWithAccessionedSequence:9662794] p-S,T-ADAM17(215-?) [plasma membrane] [Homo sapiens] [EntityWithAccessionedSequence:9662835] ADAM17 [Golgi membrane] [Homo sapiens] [EntityWithAccessionedSequence:9662839] ADAM17(215-824) [Golgi membrane] [Homo sapiens] [EntityWithAccessionedSequence:9663048] ADAM17(215-824) [plasma membrane] [Homo sapiens]
(referenceSequence)	[ModifiedResidue:9662819] O-phospho-L-serine at unknown position [ModifiedResidue:9662864] O-phospho-L-threonine at unknown position
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No pathways have been reviewed or authored by UniProt:P78536 ADAM17 (49678)