{"results":[{"entryType":"UniProtKB reviewed (Swiss-Prot)","primaryAccession":"P78536","secondaryAccessions":["O60226"],"uniProtkbId":"ADA17_HUMAN","entryAudit":{"firstPublicDate":"2001-06-20","lastAnnotationUpdateDate":"2026-09-02","lastSequenceUpdateDate":"1997-05-01","entryVersion":254,"sequenceVersion":1},"annotationScore":5.0,"organism":{"scientificName":"Homo sapiens","commonName":"Human","taxonId":9606,"lineage":["Eukaryota","Metazoa","Chordata","Craniata","Vertebrata","Euteleostomi","Mammalia","Eutheria","Euarchontoglires","Primates","Haplorrhini","Catarrhini","Hominidae","Homo"]},"proteinExistence":"1: Evidence at protein level","proteinDescription":{"recommendedName":{"fullName":{"value":"Disintegrin and metalloproteinase domain-containing protein 17"},"shortNames":[{"value":"ADAM 17"}],"ecNumbers":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12441351"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"20592283"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24227843"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28923481"}],"value":"3.4.24.86"}]},"alternativeNames":[{"fullName":{"value":"Snake venom-like protease"}},{"fullName":{"value":"TNF-alpha convertase"}},{"fullName":{"value":"TNF-alpha-converting enzyme"}}],"cdAntigenNames":[{"value":"CD156b"}],"flag":"Precursor"},"genes":[{"geneName":{"evidences":[{"evidenceCode":"ECO:0000312","source":"HGNC","id":"HGNC:195"}],"value":"ADAM17"},"synonyms":[{"value":"CSVP"},{"value":"TACE"}]}],"comments":[{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q9Z0F8"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12441351"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"20592283"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24226769"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24227843"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24337742"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26876177"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28060820"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28923481"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"36078095"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"38771644"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"9034191"}],"value":"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, PubMed:38771644). 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, PubMed:38771644). 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)"}],"commentType":"FUNCTION"},{"commentType":"CATALYTIC ACTIVITY","reaction":{"name":"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.","ecNumber":"3.4.24.86","evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12441351"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"20592283"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24227843"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28923481"}]}},{"commentType":"COFACTOR","cofactors":[{"name":"Zn(2+)","evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"9520379"}],"cofactorCrossReference":{"database":"ChEBI","id":"CHEBI:29105"}}],"note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"9520379"}],"value":"Binds 1 zinc ion per subunit."}]}},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12441351"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"20188673"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29897333"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"36078095"}],"value":"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)"}],"commentType":"SUBUNIT"},{"commentType":"INTERACTION","interactions":[{"interactantOne":{"uniProtKBAccession":"P78536","intActId":"EBI-78188"},"interactantTwo":{"uniProtKBAccession":"Q02410","geneName":"APBA1","intActId":"EBI-368690"},"numberOfExperiments":2,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P78536","intActId":"EBI-78188"},"interactantTwo":{"uniProtKBAccession":"Q99767","geneName":"APBA2","intActId":"EBI-81711"},"numberOfExperiments":2,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P78536","intActId":"EBI-78188"},"interactantTwo":{"uniProtKBAccession":"Q12959","geneName":"DLG1","intActId":"EBI-357481"},"numberOfExperiments":9,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P78536","intActId":"EBI-78188"},"interactantTwo":{"uniProtKBAccession":"Q15700","geneName":"DLG2","intActId":"EBI-80426"},"numberOfExperiments":2,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P78536","intActId":"EBI-78188"},"interactantTwo":{"uniProtKBAccession":"Q92796","geneName":"DLG3","intActId":"EBI-80440"},"numberOfExperiments":2,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P78536","intActId":"EBI-78188"},"interactantTwo":{"uniProtKBAccession":"P78352","geneName":"DLG4","intActId":"EBI-80389"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P78536","intActId":"EBI-78188"},"interactantTwo":{"uniProtKBAccession":"Q68DX3","geneName":"FRMPD2","intActId":"EBI-53993476"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P78536","intActId":"EBI-78188"},"interactantTwo":{"uniProtKBAccession":"Q13585","geneName":"GPR50","intActId":"EBI-8550965"},"numberOfExperiments":2,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P78536","intActId":"EBI-78188"},"interactantTwo":{"uniProtKBAccession":"A4D2P6","geneName":"GRID2IP","intActId":"EBI-15893226"},"numberOfExperiments":2,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P78536","intActId":"EBI-78188"},"interactantTwo":{"uniProtKBAccession":"Q9Y3R0","geneName":"GRIP1","intActId":"EBI-5349621"},"numberOfExperiments":4,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P78536","intActId":"EBI-78188"},"interactantTwo":{"uniProtKBAccession":"Q9C0E4","geneName":"GRIP2","intActId":"EBI-949557"},"numberOfExperiments":5,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P78536","intActId":"EBI-78188"},"interactantTwo":{"uniProtKBAccession":"Q14005","geneName":"IL16","intActId":"EBI-2831580"},"numberOfExperiments":2,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P78536","intActId":"EBI-78188"},"interactantTwo":{"uniProtKBAccession":"P05556","geneName":"ITGB1","intActId":"EBI-703066"},"numberOfExperiments":2,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P78536","intActId":"EBI-78188"},"interactantTwo":{"uniProtKBAccession":"Q8TBB1","geneName":"LNX1","intActId":"EBI-739832"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P78536","intActId":"EBI-78188"},"interactantTwo":{"uniProtKBAccession":"Q13257","geneName":"MAD2L1","intActId":"EBI-78203"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P78536","intActId":"EBI-78188"},"interactantTwo":{"uniProtKBAccession":"Q86UL8","geneName":"MAGI2","intActId":"EBI-311035"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P78536","intActId":"EBI-78188"},"interactantTwo":{"uniProtKBAccession":"O75970","geneName":"MPDZ","intActId":"EBI-821405"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P78536","intActId":"EBI-78188"},"interactantTwo":{"uniProtKBAccession":"Q86UT5","geneName":"NHERF4","intActId":"EBI-8744528"},"numberOfExperiments":2,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P78536","intActId":"EBI-78188"},"interactantTwo":{"uniProtKBAccession":"Q8NI35","geneName":"PATJ","intActId":"EBI-724390"},"numberOfExperiments":9,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P78536","intActId":"EBI-78188"},"interactantTwo":{"uniProtKBAccession":"Q14160","geneName":"SCRIB","intActId":"EBI-357345"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P78536","intActId":"EBI-78188"},"interactantTwo":{"uniProtKBAccession":"Q07157","geneName":"TJP1","intActId":"EBI-79553"},"numberOfExperiments":2,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P78536","intActId":"EBI-78188"},"interactantTwo":{"uniProtKBAccession":"Q9P202","geneName":"WHRN","intActId":"EBI-310886"},"numberOfExperiments":2,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P78536","intActId":"EBI-78188"},"interactantTwo":{"uniProtKBAccession":"Q80WQ6","geneName":"Rhbdf2","intActId":"EBI-647271"},"numberOfExperiments":2,"organismDiffer":true}]},{"commentTy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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). Expressed in the hair cortex, and in the inner root sheath and outer root sheath of hair follicle (PubMed:38771644)"}],"commentType":"TISSUE SPECIFICITY"},{"texts":[{"value":"In arthritis-affected cartilage"}],"commentType":"INDUCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"}],"value":"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)"}],"commentType":"DOMAIN"},{"texts":[{"value":"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"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"}],"value":"The precursor is cleaved by a furin endopeptidase"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12058067"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12621058"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"20188673"}],"value":"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"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"38771644"}],"value":"Ubiquitinated by the E3 ligase TRIM47 leading to proteasomal degradation"}],"commentType":"PTM"},{"commentType":"DISEASE","disease":{"diseaseId":"Hypotrichosis 16","diseaseAccession":"DI-07146","acronym":"HYPT16","description":"A form of hypotrichosis, a condition characterized by the presence of less than the normal amount of hair and abnormal hair follicles and shafts, which are thin and atrophic. The extent of scalp and body hair involvement can be very variable, within as well as between families. HYPT16 is an autosomal dominant, generalized form characterized by fragile, thin and woolly scalp hair, and patchy hair loss on other parts of the body. Slow growth results in complete hair loss later in life, although female patients may have only scalp affected.","diseaseCrossReference":{"database":"MIM","id":"621490"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"38771644"}]},"note":{"texts":[{"value":"The disease is caused by variants affecting the gene represented in this entry"}]}},{"commentType":"DISEASE","disease":{"diseaseId":"Inflammatory skin and bowel disease, neonatal, 1","diseaseAccession":"DI-03306","acronym":"NISBD1","description":"A disorder characterized by inflammatory features with neonatal onset, involving the skin, hair, and gut. The skin lesions involve perioral and perianal erythema, psoriasiform erythroderma, with flares of erythema, scaling, and widespread pustules. Gastrointestinal symptoms include malabsorptive diarrhea that is exacerbated by intercurrent gastrointestinal infections. 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