ID ADA17_HUMAN Reviewed; 824 AA. AC P78536; O60226; DT 20-JUN-2001, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-1997, sequence version 1. DT 02-SEP-2026, entry version 254. DE RecName: Full=Disintegrin and metalloproteinase domain-containing protein 17; DE Short=ADAM 17; DE EC=3.4.24.86 {ECO:0000269|PubMed:12441351, ECO:0000269|PubMed:20592283, ECO:0000269|PubMed:24227843, ECO:0000269|PubMed:28923481}; DE AltName: Full=Snake venom-like protease; DE AltName: Full=TNF-alpha convertase; DE AltName: Full=TNF-alpha-converting enzyme; DE AltName: CD_antigen=CD156b; DE Flags: Precursor; GN Name=ADAM17 {ECO:0000312|HGNC:HGNC:195}; Synonyms=CSVP, TACE; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM A), PARTIAL PROTEIN SEQUENCE, AND RP FUNCTION. RC TISSUE=Leukocyte, and Monocyte; RX PubMed=9034191; DOI=10.1038/385733a0; RA Moss M.L., Jin S.-L.C., Milla M.E., Burkhart W., Carter H.L., Chen W.-J., RA Clay W.C., Didsbury J.R., Hassler D., Hoffman C.R., Kost T.A., RA Lambert M.H., Leesnitzer M.A., McCauley P., McGeehan G., Mitchell J., RA Moyer M., Pahel G., Rocque W., Overton L.K., Schoenen F., Seaton T., RA Su J.-L., Warner J., Willard D., Becherer J.D.; RT "Cloning of a disintegrin metalloproteinase that processes precursor RT tumour-necrosis factor-alpha."; RL Nature 385:733-736(1997). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS A AND B). RX PubMed=9034190; DOI=10.1038/385729a0; RA Black R.A., Rauch C.T., Kozlosky C.J., Peschon J.J., Slack J.L., RA Wolfson M.F., Castner B.J., Stocking K.L., Reddy P., Srinivasan S., RA Nelson N., Bioani N., Schooley K.A., Gerhart M., Davis R., Fitzner J.N., RA Johnson R.S., Paxton R.J., March C.J., Cerretti D.P.; RT "A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha RT from cells."; RL Nature 385:729-733(1997). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM A). RC TISSUE=Cartilage; RX PubMed=9574564; RA Patel I.R., Attur M.G., Patel R.N., Stuchin S.A., Abagyan R.A., RA Abramson S.B., Amin A.R.; RT "TNF-alpha convertase enzyme from human arthritis-affected cartilage: RT isolation of cDNA by differential display, expression of the active enzyme, RT and regulation of TNF-alpha."; RL J. Immunol. 160:4570-4579(1998). RN [4] RP PHOSPHORYLATION AT THR-735. RX PubMed=12058067; DOI=10.1091/mbc.01-11-0561; RA Diaz-Rodriguez E., Montero J.C., Esparis-Ogando A., Yuste L., Pandiella A.; RT "Extracellular signal-regulated kinase phosphorylates tumor necrosis factor RT alpha-converting enzyme at threonine 735: a potential role in regulated RT shedding."; RL Mol. Biol. Cell 13:2031-2044(2002). RN [5] RP FUNCTION, CATALYTIC ACTIVITY, AND INTERACTION WITH MUC1. RX PubMed=12441351; DOI=10.1074/jbc.m208326200; RA Thathiah A., Blobel C.P., Carson D.D.; RT "Tumor necrosis factor-alpha converting enzyme/ADAM 17 mediates MUC1 RT shedding."; RL J. Biol. Chem. 278:3386-3394(2003). RN [6] RP PHOSPHORYLATION AT SER-819. RX PubMed=12621058; DOI=10.1074/jbc.m300331200; RA Fan H., Turck C.W., Derynck R.; RT "Characterization of growth factor-induced serine phosphorylation of tumor RT necrosis factor-alpha converting enzyme and of an alternatively translated RT polypeptide."; RL J. Biol. Chem. 278:18617-18627(2003). RN [7] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-791, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026; RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.; RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling RT networks."; RL Cell 127:635-648(2006). RN [8] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-791, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [9] RP ROLE IN PROTEOLYTICAL RELEASE OF JAM3. RX PubMed=20592283; DOI=10.4049/jimmunol.1000556; RA Rabquer B.J., Amin M.A., Teegala N., Shaheen M.K., Tsou P.S., Ruth J.H., RA Lesch C.A., Imhof B.A., Koch A.E.; RT "Junctional adhesion molecule-C is a soluble mediator of angiogenesis."; RL J. Immunol. 185:1777-1785(2010). RN [10] RP PHOSPHORYLATION AT THR-735, AND INTERACTION WITH MAPK14. RX PubMed=20188673; DOI=10.1016/j.molcel.2010.01.034; RA Xu P., Derynck R.; RT "Direct activation of TACE-mediated ectodomain shedding by p38 MAP kinase RT regulates EGF receptor-dependent cell proliferation."; RL Mol. Cell 37:551-566(2010). RN [11] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-791, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [12] RP INVOLVEMENT IN NISBD1. RX PubMed=22010916; DOI=10.1056/nejmoa1100721; RA Blaydon D.C., Biancheri P., Di W.L., Plagnol V., Cabral R.M., Brooke M.A., RA van Heel D.A., Ruschendorf F., Toynbee M., Walne A., O'Toole E.A., RA Martin J.E., Lindley K., Vulliamy T., Abrams D.J., MacDonald T.T., RA Harper J.I., Kelsell D.P.; RT "Inflammatory skin and bowel disease linked to ADAM17 deletion."; RL N. Engl. J. Med. 365:1502-1508(2011). RN [13] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-791, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21406692; DOI=10.1126/scisignal.2001570; RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.; RT "System-wide temporal characterization of the proteome and phosphoproteome RT of human embryonic stem cell differentiation."; RL Sci. Signal. 4:RS3-RS3(2011). RN [14] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-761 AND SER-791, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [15] RP FUNCTION. RX PubMed=24226769; DOI=10.1038/nature12723; RA Boskovski M.T., Yuan S., Pedersen N.B., Goth C.K., Makova S., Clausen H., RA Brueckner M., Khokha M.K.; RT "The heterotaxy gene GALNT11 glycosylates Notch to orchestrate cilia type RT and laterality."; RL Nature 504:456-459(2013). RN [16] RP FUNCTION, AND TISSUE SPECIFICITY. RX PubMed=24337742; DOI=10.4049/jimmunol.1301024; RA Lajoie L., Congy-Jolivet N., Bolzec A., Gouilleux-Gruart V., Sicard E., RA Sung H.C., Peiretti F., Moreau T., Vie H., Clemenceau B., Thibault G.; RT "ADAM17-mediated shedding of FcgammaRIIIA on human NK cells: identification RT of the cleavage site and relationship with activation."; RL J. Immunol. 192:741-751(2014). RN [17] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-791, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [18] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=24227843; DOI=10.1128/jvi.02202-13; RA Heurich A., Hofmann-Winkler H., Gierer S., Liepold T., Jahn O., RA Poehlmann S.; RT "TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by RT TMPRSS2 augments entry driven by the severe acute respiratory syndrome RT coronavirus spike protein."; RL J. Virol. 88:1293-1307(2014). RN [19] RP FUNCTION. RX PubMed=26876177; DOI=10.1016/j.celrep.2016.01.053; RA Lokau J., Nitz R., Agthe M., Monhasery N., Aparicio-Siegmund S., RA Schumacher N., Wolf J., Moeller-Hackbarth K., Waetzig G.H., Groetzinger J., RA Mueller-Newen G., Rose-John S., Scheller J., Garbers C.; RT "Proteolytic Cleavage Governs Interleukin-11 Trans-signaling."; RL Cell Rep. 14:1761-1773(2016). RN [20] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=28923481; DOI=10.1016/j.neulet.2017.09.034; RA Feuerbach D., Schindler P., Barske C., Joller S., Beng-Louka E., RA Worringer K.A., Kommineni S., Kaykas A., Ho D.J., Ye C., Welzenbach K., RA Elain G., Klein L., Brzak I., Mir A.K., Farady C.J., Aichholz R., Popp S., RA George N., Neumann U.; RT "ADAM17 is the main sheddase for the generation of human triggering RT receptor expressed in myeloid cells (hTREM2) ectodomain and cleaves TREM2 RT after Histidine 157."; RL Neurosci. Lett. 660:109-114(2017). RN [21] RP FUNCTION. RX PubMed=28060820; DOI=10.1371/journal.pbio.2000080; RA Riethmueller S., Somasundaram P., Ehlers J.C., Hung C.W., Flynn C.M., RA Lokau J., Agthe M., Duesterhoeft S., Zhu Y., Groetzinger J., Lorenzen I., RA Koudelka T., Yamamoto K., Pickhinke U., Wichert R., Becker-Pauly C., RA Raedisch M., Albrecht A., Hessefort M., Stahnke D., Unverzagt C., RA Rose-John S., Tholey A., Garbers C.; RT "Proteolytic Origin of the Soluble Human IL-6R In Vivo and a Decisive Role RT of N-Glycosylation."; RL PLoS Biol. 15:e2000080-e2000080(2017). RN [22] RP INTERACTION WITH RHBDF1 AND RHBDF2. RX PubMed=29897333; DOI=10.7554/elife.35032; RA Oikonomidi I., Burbridge E., Cavadas M., Sullivan G., Collis B., RA Naegele H., Clancy D., Brezinova J., Hu T., Bileck A., Gerner C., RA Bolado A., von Kriegsheim A., Martin S.J., Steinberg F., Strisovsky K., RA Adrain C.; RT "iTAP, a novel iRhom interactor, controls TNF secretion by policing the RT stability of iRhom/TACE."; RL Elife 7:0-0(2018). RN [23] RP INTERACTION WITH FRMD8; RHBDF1 AND RHBDF2. RX PubMed=29897336; DOI=10.7554/elife.35012; RA Kuenzel U., Grieve A.G., Meng Y., Sieber B., Cowley S.A., Freeman M.; RT "FRMD8 promotes inflammatory and growth factor signalling by stabilising RT the iRhom/ADAM17 sheddase complex."; RL Elife 7:0-0(2018). RN [24] RP FUNCTION, INTERACTION WITH TSPAN8, AND SUBCELLULAR LOCATION. RX PubMed=36078095; DOI=10.3390/cells11172683; RA Mueller M., Saunders C., Senftleben A., Heidbuechel J.P.W., Halwachs B., RA Bolik J., Hedemann N., Roeder C., Bauerschlag D., Rose-John S., RA Schmidt-Arras D.; RT "Tetraspanin 8 Subfamily Members Regulate Substrate-Specificity of a RT Disintegrin and Metalloprotease 17."; RL Cells 11:0-0(2022). RN [25] RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 219-473 IN COMPLEX WITH ZINC, RP COFACTOR, ACTIVE SITE, AND DISULFIDE BONDS. RX PubMed=9520379; DOI=10.1073/pnas.95.7.3408; RA Maskos K., Fernandez-Catalan C., Huber R., Bourenkov G.P., Bartunik H., RA Ellestad G.A., Reddy P., Wolfson M.F., Rauch C.T., Castner B.J., Davis R., RA Clarke H.R.G., Petersen M., Fitzner J.N., Cerretti D.P., March C.J., RA Paxton R.J., Black R.A., Bode W.; RT "Crystal structure of the catalytic domain of human tumor necrosis factor- RT alpha-converting enzyme."; RL Proc. Natl. Acad. Sci. U.S.A. 95:3408-3412(1998). RN [26] RP VARIANT HYPT16 ASN-647, CHARACTERIZATION OF VARIANT HYPT16 ASN-647, RP INVOLVEMENT IN HYPT16, FUNCTION, TISSUE SPECIFICITY, AND UBIQUITINATION BY RP TRIM47. RX PubMed=38771644; DOI=10.1172/jci.insight.177588; RA Wang X., Pan C., Zheng L., Wang J., Zou Q., Sun P., Zhou K., Zhao A., RA Cao Q., He W., Wang Y., Cheng R., Yao Z., Zhang S., Zhang H., Li M.; RT "ADAM17 variant causes hair loss via ubiquitin ligase TRIM47-mediated RT degradation."; RL JCI Insight 9:0-0(2024). CC -!- FUNCTION: Transmembrane metalloprotease which mediates the ectodomain CC shedding of a myriad of transmembrane proteins including adhesion CC proteins, growth factor precursors and cytokines important for CC inflammation and immunity (PubMed:24226769, PubMed:24227843, CC PubMed:28060820, PubMed:28923481, PubMed:38771644). Cleaves the CC membrane-bound precursor of TNF to its mature soluble form CC (PubMed:36078095, PubMed:9034191). Responsible for the proteolytical CC release of soluble JAM3 from endothelial cells surface CC (PubMed:20592283). Responsible for the proteolytic release of several CC other cell-surface proteins, including p75 TNF-receptor, interleukin 1 CC receptor type II, p55 TNF-receptor, transforming growth factor-alpha, CC L-selectin, growth hormone receptor, MUC1 and the amyloid precursor CC protein (PubMed:12441351). Acts as an activator of Notch pathway by CC mediating cleavage of Notch, generating the membrane-associated CC intermediate fragment called Notch extracellular truncation (NEXT) CC (PubMed:24226769, PubMed:38771644). Plays a role in the proteolytic CC processing of ACE2 (PubMed:24227843). Plays a role in hemostasis CC through shedding of GP1BA, the platelet glycoprotein Ib alpha chain (By CC similarity). Mediates the proteolytic cleavage of LAG3, leading to CC release the secreted form of LAG3 (By similarity). Mediates the CC proteolytic cleavage of IL6R, leading to the release of secreted form CC of IL6R (PubMed:26876177, PubMed:28060820). Mediates the proteolytic CC cleavage and shedding of FCGR3A upon NK cell stimulation, a mechanism CC that allows for increased NK cell motility and detachment from CC opsonized target cells. Cleaves TREM2, resulting in shedding of the CC TREM2 ectodomain (PubMed:28923481). {ECO:0000250|UniProtKB:Q9Z0F8, CC ECO:0000269|PubMed:12441351, ECO:0000269|PubMed:20592283, CC ECO:0000269|PubMed:24226769, ECO:0000269|PubMed:24227843, CC ECO:0000269|PubMed:24337742, ECO:0000269|PubMed:26876177, CC ECO:0000269|PubMed:28060820, ECO:0000269|PubMed:28923481, CC ECO:0000269|PubMed:36078095, ECO:0000269|PubMed:38771644, CC ECO:0000269|PubMed:9034191}. CC -!- CATALYTIC ACTIVITY: CC Reaction=Narrow endopeptidase specificity. Cleaves Pro-Leu-Ala-Gln- CC Ala-|-Val-Arg-Ser-Ser-Ser in the membrane-bound, 26-kDa form of tumor CC necrosis factor alpha (TNFalpha). Similarly cleaves other membrane- CC anchored, cell-surface proteins to 'shed' the extracellular domains.; CC EC=3.4.24.86; Evidence={ECO:0000269|PubMed:12441351, CC ECO:0000269|PubMed:20592283, ECO:0000269|PubMed:24227843, CC ECO:0000269|PubMed:28923481}; CC -!- COFACTOR: CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105; CC Evidence={ECO:0000269|PubMed:9520379}; CC Note=Binds 1 zinc ion per subunit. {ECO:0000269|PubMed:9520379}; CC -!- SUBUNIT: Interacts with MAD2L1, MAPK14 and MUC1 (PubMed:12441351, CC PubMed:20188673). Interacts with iRhom1/RHBDF1 and iRhom2/RHBDF2 CC (PubMed:29897333). Interacts with FRMD8 via its interaction with CC iRhom1/RHBDF1 and iRhom2/RHBDF2 (PubMed:29897333). Interacts with CC TSPAN8 (PubMed:36078095). {ECO:0000269|PubMed:12441351, CC ECO:0000269|PubMed:20188673, ECO:0000269|PubMed:29897333, CC ECO:0000269|PubMed:36078095}. CC -!- INTERACTION: CC P78536; Q02410: APBA1; NbExp=2; IntAct=EBI-78188, EBI-368690; CC P78536; Q99767: APBA2; NbExp=2; IntAct=EBI-78188, EBI-81711; CC P78536; Q12959: DLG1; NbExp=9; IntAct=EBI-78188, EBI-357481; CC P78536; Q15700: DLG2; NbExp=2; IntAct=EBI-78188, EBI-80426; CC P78536; Q92796: DLG3; NbExp=2; IntAct=EBI-78188, EBI-80440; CC P78536; P78352: DLG4; NbExp=3; IntAct=EBI-78188, EBI-80389; CC P78536; Q68DX3: FRMPD2; NbExp=3; IntAct=EBI-78188, EBI-53993476; CC P78536; Q13585: GPR50; NbExp=2; IntAct=EBI-78188, EBI-8550965; CC P78536; A4D2P6: GRID2IP; NbExp=2; IntAct=EBI-78188, EBI-15893226; CC P78536; Q9Y3R0: GRIP1; NbExp=4; IntAct=EBI-78188, EBI-5349621; CC P78536; Q9C0E4: GRIP2; NbExp=5; IntAct=EBI-78188, EBI-949557; CC P78536; Q14005: IL16; NbExp=2; IntAct=EBI-78188, EBI-2831580; CC P78536; P05556: ITGB1; NbExp=2; IntAct=EBI-78188, EBI-703066; CC P78536; Q8TBB1: LNX1; NbExp=3; IntAct=EBI-78188, EBI-739832; CC P78536; Q13257: MAD2L1; NbExp=3; IntAct=EBI-78188, EBI-78203; CC P78536; Q86UL8: MAGI2; NbExp=3; IntAct=EBI-78188, EBI-311035; CC P78536; O75970: MPDZ; NbExp=3; IntAct=EBI-78188, EBI-821405; CC P78536; Q86UT5: NHERF4; NbExp=2; IntAct=EBI-78188, EBI-8744528; CC P78536; Q8NI35: PATJ; NbExp=9; IntAct=EBI-78188, EBI-724390; CC P78536; Q14160: SCRIB; NbExp=3; IntAct=EBI-78188, EBI-357345; CC P78536; Q07157: TJP1; NbExp=2; IntAct=EBI-78188, EBI-79553; CC P78536; Q9P202: WHRN; NbExp=2; IntAct=EBI-78188, EBI-310886; CC P78536; Q80WQ6: Rhbdf2; Xeno; NbExp=2; IntAct=EBI-78188, EBI-647271; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:36078095}; CC Single-pass type I membrane protein. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=A; CC IsoId=P78536-1; Sequence=Displayed; CC Name=B; CC IsoId=P78536-2; Sequence=VSP_005478; CC -!- TISSUE SPECIFICITY: Ubiquitously expressed. Expressed at highest levels CC in adult heart, placenta, skeletal muscle, pancreas, spleen, thymus, CC prostate, testes, ovary and small intestine, and in fetal brain, lung, CC liver and kidney. Expressed in natural killer cells (at protein level) CC (PubMed:24337742). Expressed in the hair cortex, and in the inner root CC sheath and outer root sheath of hair follicle (PubMed:38771644). CC {ECO:0000269|PubMed:24337742, ECO:0000269|PubMed:38771644}. CC -!- INDUCTION: In arthritis-affected cartilage. CC -!- DOMAIN: Must be membrane anchored to cleave the different substrates. CC The cytoplasmic domain is not required for the this activity. Only the CC catalytic domain is essential to shed TNF and p75 TNFR (By similarity). CC {ECO:0000250}. CC -!- DOMAIN: The conserved cysteine present in the cysteine-switch motif CC binds the catalytic zinc ion, thus inhibiting the enzyme. The CC dissociation of the cysteine from the zinc ion upon the activation- CC peptide release activates the enzyme. CC -!- PTM: The precursor is cleaved by a furin endopeptidase. {ECO:0000250}. CC -!- PTM: Phosphorylated. Stimulation by growth factor or phorbol 12- CC myristate 13-acetate induces phosphorylation of Ser-819 but decreases CC phosphorylation of Ser-791. Phosphorylation at Thr-735 by MAPK14 is CC required for ADAM17-mediated ectodomain shedding. CC {ECO:0000269|PubMed:12058067, ECO:0000269|PubMed:12621058, CC ECO:0000269|PubMed:20188673}. CC -!- PTM: Ubiquitinated by the E3 ligase TRIM47 leading to proteasomal CC degradation. {ECO:0000269|PubMed:38771644}. CC -!- DISEASE: Hypotrichosis 16 (HYPT16) [MIM:621490]: A form of CC hypotrichosis, a condition characterized by the presence of less than CC the normal amount of hair and abnormal hair follicles and shafts, which CC are thin and atrophic. The extent of scalp and body hair involvement CC can be very variable, within as well as between families. HYPT16 is an CC autosomal dominant, generalized form characterized by fragile, thin and CC woolly scalp hair, and patchy hair loss on other parts of the body. CC Slow growth results in complete hair loss later in life, although CC female patients may have only scalp affected. CC {ECO:0000269|PubMed:38771644}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Inflammatory skin and bowel disease, neonatal, 1 (NISBD1) CC [MIM:614328]: A disorder characterized by inflammatory features with CC neonatal onset, involving the skin, hair, and gut. The skin lesions CC involve perioral and perianal erythema, psoriasiform erythroderma, with CC flares of erythema, scaling, and widespread pustules. Gastrointestinal CC symptoms include malabsorptive diarrhea that is exacerbated by CC intercurrent gastrointestinal infections. The hair is short or broken, CC and the eyelashes and eyebrows are wiry and disorganized. CC {ECO:0000269|PubMed:22010916}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- WEB RESOURCE: Name=Wikipedia; Note=Tumor necrosis factor CC alpha-converting enzyme entry; CC URL="https://en.wikipedia.org/wiki/Tumor_Necrosis_Factor_Alpha_Converting_Enzyme"; CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/572/ADAM17"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U86755; AAB51586.1; -; mRNA. DR EMBL; U69611; AAB51514.1; -; mRNA. DR EMBL; U69612; AAB53014.1; -; mRNA. DR EMBL; U92649; AAC39721.1; -; mRNA. DR CCDS; CCDS1665.1; -. [P78536-1] DR RefSeq; NP_003174.3; NM_003183.6. [P78536-1] DR PDB; 1BKC; X-ray; 2.00 A; A/C/E/I=219-474. DR PDB; 1ZXC; X-ray; 2.28 A; A/B=215-477. DR PDB; 2A8H; X-ray; 2.30 A; A/B=215-477. DR PDB; 2DDF; X-ray; 1.70 A; A/B=218-474. DR PDB; 2FV5; X-ray; 2.10 A; A/B=216-475. DR PDB; 2FV9; X-ray; 2.02 A; A/B=218-475. DR PDB; 2I47; X-ray; 1.90 A; A/B/C/D=212-493. DR PDB; 2M2F; NMR; -; A=581-642. DR PDB; 2OI0; X-ray; 2.00 A; A=216-477. DR PDB; 3B92; X-ray; 2.00 A; A=216-474. DR PDB; 3CKI; X-ray; 2.30 A; A=219-474. DR PDB; 3E8R; X-ray; 1.90 A; A/B=215-477. DR PDB; 3EDZ; X-ray; 1.90 A; A/B=215-477. DR PDB; 3EWJ; X-ray; 1.80 A; A/B=215-477. DR PDB; 3G42; X-ray; 2.10 A; A/B/C/D=212-492. DR PDB; 3KMC; X-ray; 1.80 A; A/B=215-476. DR PDB; 3KME; X-ray; 1.85 A; A/B=215-476. DR PDB; 3L0T; X-ray; 1.92 A; A/B=215-476. DR PDB; 3L0V; X-ray; 1.75 A; A/B=215-476. DR PDB; 3LE9; X-ray; 1.85 A; A/B=215-476. DR PDB; 3LEA; X-ray; 2.00 A; A/B=215-476. DR PDB; 3LGP; X-ray; 1.90 A; A/B=215-476. DR PDB; 3O64; X-ray; 1.88 A; A/B=215-476. DR PDB; 8CQY; X-ray; 1.70 A; B=813-824. DR PDB; 8SNL; EM; 2.78 A; A=1-824. DR PDB; 8SNM; EM; 3.84 A; A=1-214, B=215-824. DR PDB; 8SNN; EM; 2.32 A; A=215-824. DR PDB; 8SNO; EM; 2.78 A; A=215-824. DR PDB; 9E6K; EM; 3.15 A; C=530-644. DR PDB; 9O54; EM; 3.50 A; A=1-477. DR PDB; 9O58; EM; 3.53 A; A=28-824. DR AlphaFoldDB; P78536; -. DR BMRB; P78536; -. DR EMDB; EMD-40628; -. DR EMDB; EMD-40629; -. DR EMDB; EMD-40630; -. DR EMDB; EMD-40631; -. DR EMDB; EMD-47571; -. DR EMDB; EMD-70123; -. DR EMDB; EMD-70127; -. DR EMDB; EMD-72319; -. DR EMDB; EMD-72322; -. DR MDposit; P78536; -. DR SMR; P78536; -. DR BioGRID; 112731; 147. DR CORUM; P78536; -. DR DIP; DIP-31044N; -. DR FunCoup; P78536; 1854. DR IntAct; P78536; 131. DR MINT; P78536; -. DR NDEx; IQUERY-CP-ADAM17; 15 NDEx IQuery Curated Pathways. DR STRING; 9606.ENSP00000309968; -. DR BindingDB; P78536; -. DR ChEMBL; CHEMBL3706; -. DR DrugBank; DB07189; (1S,3R,6S)-4-oxo-6-{4-[(2-phenylquinolin-4-yl)methoxy]phenyl}-5-azaspiro[2.4]heptane-1-carboxylic acid. DR DrugBank; DB07145; (2R)-N-HYDROXY-2-[(3S)-3-METHYL-3-{4-[(2-METHYLQUINOLIN-4-YL)METHOXY]PHENYL}-2-OXOPYRROLIDIN-1-YL]PROPANAMIDE. DR DrugBank; DB06943; (3S)-1-{[4-(but-2-yn-1-yloxy)phenyl]sulfonyl}pyrrolidine-3-thiol. DR DrugBank; DB07964; (3S)-4-{[4-(BUT-2-YNYLOXY)PHENYL]SULFONYL}-N-HYDROXY-2,2-DIMETHYLTHIOMORPHOLINE-3-CARBOXAMIDE. DR DrugBank; DB07079; 3-{[4-(but-2-yn-1-yloxy)phenyl]sulfonyl}propane-1-thiol. DR DrugBank; DB07121; 4-({4-[(4-AMINOBUT-2-YNYL)OXY]PHENYL}SULFONYL)-N-HYDROXY-2,2-DIMETHYLTHIOMORPHOLINE-3-CARBOXAMIDE. DR DrugBank; DB21288; Aderbasib. DR DrugBank; DB13020; Apratastat. DR DrugBank; DB07147; methyl (1R,2S)-2-(hydroxycarbamoyl)-1-{4-[(2-methylquinolin-4-yl)methoxy]benzyl}cyclopropanecarboxylate. DR DrugBank; DB07233; N-{[4-(but-2-yn-1-yloxy)phenyl]sulfonyl}-5-methyl-D-tryptophan. DR DrugCentral; P78536; -. DR GuidetoPHARMACOLOGY; 1662; -. DR MEROPS; M12.217; -. DR TCDB; 8.A.77.1.2; the sheddase (sheddase) family. DR GlyConnect; P78536; 18 N-Linked glycans (5 sites). DR GlyCosmos; P78536; 9 sites, 20 glycans. DR GlyGen; P78536; 13 sites, 57 N-linked glycans (9 sites), 1 O-linked glycan (3 sites). DR iPTMnet; P78536; -. DR PhosphoSitePlus; P78536; -. DR SwissPalm; P78536; -. DR BioMuta; ADAM17; -. DR DMDM; 14423632; -. DR CPTAC; CPTAC-1561; -. DR CPTAC; CPTAC-5968; -. DR jPOST; P78536; -. DR MassIVE; P78536; -. DR PaxDb; 9606-ENSP00000309968; -. DR PeptideAtlas; P78536; -. DR ProteomicsDB; 57637; -. [P78536-1] DR ProteomicsDB; 57638; -. [P78536-2] DR Pumba; P78536; -. DR ABCD; P78536; 34 sequenced antibodies. DR Antibodypedia; 2540; 978 antibodies from 51 providers. DR DNASU; 6868; -. DR Ensembl; ENST00000310823.8; ENSP00000309968.3; ENSG00000151694.16. [P78536-1] DR GeneID; 6868; -. DR KEGG; hsa:6868; -. DR MANE-Select; ENST00000310823.8; ENSP00000309968.3; NM_003183.6; NP_003174.3. DR UCSC; uc002qzu.5; human. [P78536-1] DR AGR; HGNC:195; -. DR ClinPGx; PA24512; -. DR CTD; 6868; -. DR DisGeNET; 6868; -. DR GeneCards; ADAM17; -. DR HGNC; HGNC:195; ADAM17. DR HPA; ENSG00000151694; Low tissue specificity. DR MalaCards; ADAM17; -. DR MIM; 603639; gene. DR MIM; 614328; phenotype. DR MIM; 621490; phenotype. DR NIAGADS; ENSG00000151694; -. DR OpenTargets; ENSG00000151694; -. DR Orphanet; 294023; Neonatal erythroderma-autoinflammation-inflammatory bowel disease syndrome. DR VEuPathDB; HostDB:ENSG00000151694; -. DR eggNOG; KOG3658; Eukaryota. DR GeneTree; ENSGT00940000155443; -. DR HOGENOM; CLU_004602_2_0_1; -. DR InParanoid; P78536; -. DR OMA; EHDPDIT; -. DR OrthoDB; 2131567at2759; -. DR PAN-GO; P78536; 4 GO annotations based on evolutionary models. DR PhylomeDB; P78536; -. DR BRENDA; 3.4.24.86; 2681. DR PathwayCommons; P78536; -. DR Reactome; R-HSA-1251985; Nuclear signaling by ERBB4. DR Reactome; R-HSA-1442490; Collagen degradation. DR Reactome; R-HSA-177929; Signaling by EGFR. DR Reactome; R-HSA-193692; Regulated proteolysis of p75NTR. DR Reactome; R-HSA-2122948; Activated NOTCH1 Transmits Signal to the Nucleus. DR Reactome; R-HSA-2644606; Constitutive Signaling by NOTCH1 PEST Domain Mutants. DR Reactome; R-HSA-2660826; Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant. DR Reactome; R-HSA-2691232; Constitutive Signaling by NOTCH1 HD Domain Mutants. DR Reactome; R-HSA-2894862; Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants. DR Reactome; R-HSA-5362798; Release of Hh-Np from the secreting cell. DR Reactome; R-HSA-75893; TNF signaling. DR Reactome; R-HSA-9662834; CD163 mediating an anti-inflammatory response. DR Reactome; R-HSA-982772; Growth hormone receptor signaling. DR SignaLink; P78536; -. DR SIGNOR; P78536; -. DR Agora; ENSG00000151694; -. DR BioGRID-ORCS; 6868; 15 hits in 1172 CRISPR screens. DR ChiTaRS; ADAM17; human. DR EvolutionaryTrace; P78536; -. DR GeneWiki; ADAM17; -. DR GenomeRNAi; 6868; -. DR Pharos; P78536; Tchem. DR PRO; PR:P78536; -. DR Proteomes; UP000005640; Chromosome 2. DR RNAct; P78536; protein. DR Bgee; ENSG00000151694; Expressed in oocyte and 209 other cell types or tissues. DR ExpressionAtlas; P78536; baseline and differential. DR GO; GO:0015629; C:actin cytoskeleton; IDA:BHF-UCL. DR GO; GO:0016324; C:apical plasma membrane; IDA:BHF-UCL. DR GO; GO:0009986; C:cell surface; IDA:BHF-UCL. DR GO; GO:0005737; C:cytoplasm; IDA:BHF-UCL. DR GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome. DR GO; GO:0000139; C:Golgi membrane; TAS:Reactome. DR GO; GO:0016020; C:membrane; HDA:UniProtKB. DR GO; GO:0045121; C:membrane raft; IDA:BHF-UCL. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0019955; F:cytokine binding; IPI:BHF-UCL. DR GO; GO:0004175; F:endopeptidase activity; IMP:UniProtKB. DR GO; GO:0005178; F:integrin binding; IPI:BHF-UCL. DR GO; GO:0005138; F:interleukin-6 receptor binding; IPI:BHF-UCL. DR GO; GO:0070573; F:metallodipeptidase activity; IEA:Ensembl. DR GO; GO:0004222; F:metalloendopeptidase activity; IDA:UniProtKB. DR GO; GO:0008237; F:metallopeptidase activity; IDA:BHF-UCL. DR GO; GO:0005112; F:Notch binding; IDA:UniProtKB. DR GO; GO:0030165; F:PDZ domain binding; IPI:BHF-UCL. DR GO; GO:0008233; F:peptidase activity; TAS:ARUK-UCL. DR GO; GO:0043120; F:tumor necrosis factor binding; IDA:ARUK-UCL. DR GO; GO:0043130; F:ubiquitin binding; IMP:UniProtKB. DR GO; GO:0042987; P:amyloid precursor protein catabolic process; IDA:ARUK-UCL. DR GO; GO:0030183; P:B cell differentiation; ISS:BHF-UCL. DR GO; GO:0007155; P:cell adhesion; IDA:BHF-UCL. DR GO; GO:0033627; P:cell adhesion mediated by integrin; IDA:BHF-UCL. DR GO; GO:0048870; P:cell motility; ISS:BHF-UCL. DR GO; GO:0071403; P:cellular response to high density lipoprotein particle stimulus; IDA:BHF-UCL. DR GO; GO:0071679; P:commissural neuron axon guidance; IMP:FlyBase. DR GO; GO:0140447; P:cytokine precursor processing; IDA:BHF-UCL. DR GO; GO:0050830; P:defense response to Gram-positive bacterium; IMP:BHF-UCL. DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; IDA:BHF-UCL. DR GO; GO:0002467; P:germinal center formation; ISS:BHF-UCL. DR GO; GO:0006509; P:membrane protein ectodomain proteolysis; IDA:UniProtKB. DR GO; GO:0120163; P:negative regulation of cold-induced thermogenesis; ISS:YuBioLab. DR GO; GO:0030512; P:negative regulation of transforming growth factor beta receptor signaling pathway; IMP:UniProtKB. DR GO; GO:0002446; P:neutrophil mediated immunity; IC:BHF-UCL. DR GO; GO:0007220; P:Notch receptor processing; IDA:UniProtKB. DR GO; GO:0007219; P:Notch signaling pathway; IBA:GO_Central. DR GO; GO:0043491; P:phosphatidylinositol 3-kinase/protein kinase B signal transduction; IMP:BHF-UCL. DR GO; GO:0043536; P:positive regulation of blood vessel endothelial cell migration; IDA:BHF-UCL. DR GO; GO:0030307; P:positive regulation of cell growth; IMP:BHF-UCL. DR GO; GO:0030335; P:positive regulation of cell migration; IDA:ARUK-UCL. DR GO; GO:0008284; P:positive regulation of cell population proliferation; IMP:BHF-UCL. DR GO; GO:0032722; P:positive regulation of chemokine production; IMP:BHF-UCL. DR GO; GO:0045742; P:positive regulation of epidermal growth factor receptor signaling pathway; IDA:BHF-UCL. DR GO; GO:1900087; P:positive regulation of G1/S transition of mitotic cell cycle; IMP:BHF-UCL. DR GO; GO:0002690; P:positive regulation of leukocyte chemotaxis; IC:BHF-UCL. DR GO; GO:0010820; P:positive regulation of T cell chemotaxis; IMP:BHF-UCL. DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IDA:BHF-UCL. DR GO; GO:1903265; P:positive regulation of tumor necrosis factor-mediated signaling pathway; IDA:ARUK-UCL. DR GO; GO:1905564; P:positive regulation of vascular endothelial cell proliferation; IDA:BHF-UCL. DR GO; GO:0002532; P:production of molecular mediator involved in inflammatory response; IEA:Ensembl. DR GO; GO:0016485; P:protein processing; IDA:ARUK-UCL. DR GO; GO:0006508; P:proteolysis; IDA:UniProtKB. DR GO; GO:0033025; P:regulation of mast cell apoptotic process; ISS:BHF-UCL. DR GO; GO:0001666; P:response to hypoxia; IDA:BHF-UCL. DR GO; GO:0032496; P:response to lipopolysaccharide; IDA:BHF-UCL. DR GO; GO:0009410; P:response to xenobiotic stimulus; ISS:BHF-UCL. DR GO; GO:0023061; P:signal release; IDA:BHF-UCL. DR GO; GO:0048536; P:spleen development; ISS:BHF-UCL. DR GO; GO:0033077; P:T cell differentiation in thymus; ISS:BHF-UCL. DR GO; GO:0035313; P:wound healing, spreading of epidermal cells; IEP:BHF-UCL. DR CDD; cd14246; ADAM17_MPD; 1. DR CDD; cd04270; ZnMc_TACE_like; 1. DR FunFam; 3.40.390.10:FF:000017; Disintegrin and metalloproteinase domain-containing protein 17; 1. DR FunFam; 4.10.70.10:FF:000003; Disintegrin and metalloproteinase domain-containing protein 17; 1. DR FunFam; 4.10.70.30:FF:000002; Disintegrin and metalloproteinase domain-containing protein 17; 1. DR Gene3D; 4.10.70.30; -; 1. DR Gene3D; 3.40.390.10; Collagenase (Catalytic Domain); 1. DR Gene3D; 4.10.70.10; Disintegrin domain; 1. DR InterPro; IPR034025; ADAM10_ADAM17. DR InterPro; IPR032029; ADAM17_MPD. DR InterPro; IPR051489; ADAM_Metalloproteinase. DR InterPro; IPR001762; Disintegrin_dom. DR InterPro; IPR036436; Disintegrin_dom_sf. DR InterPro; IPR024079; MetalloPept_cat_dom_sf. DR InterPro; IPR001590; Peptidase_M12B. DR PANTHER; PTHR45702; ADAM10/ADAM17 METALLOPEPTIDASE FAMILY MEMBER; 1. DR PANTHER; PTHR45702:SF6; DISINTEGRIN AND METALLOPROTEINASE DOMAIN-CONTAINING PROTEIN 17; 1. DR Pfam; PF16698; ADAM17_MPD; 1. DR Pfam; PF00200; Disintegrin; 1. DR Pfam; PF13574; Reprolysin_2; 1. DR SMART; SM00050; DISIN; 1. DR SUPFAM; SSF57552; Blood coagulation inhibitor (disintegrin); 1. DR SUPFAM; SSF55486; Metalloproteases ('zincins'), catalytic domain; 1. DR PROSITE; PS50215; ADAM_MEPRO; 1. DR PROSITE; PS50214; DISINTEGRIN_2; 1. DR PROSITE; PS00142; ZINC_PROTEASE; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cell membrane; KW Cleavage on pair of basic residues; Direct protein sequencing; KW Disease variant; Disulfide bond; Glycoprotein; Hydrolase; Hypotrichosis; KW Membrane; Metal-binding; Metalloprotease; Notch signaling pathway; KW Phosphoprotein; Protease; Proteomics identification; Reference proteome; KW SH3-binding; Signal; Transmembrane; Transmembrane helix; Ubl conjugation; KW Zinc; Zymogen. FT SIGNAL 1..17 FT /evidence="ECO:0000250|UniProtKB:Q9Z1K9" FT PROPEP 18..214 FT /evidence="ECO:0000269|PubMed:9034191" FT /id="PRO_0000029088" FT CHAIN 215..824 FT /note="Disintegrin and metalloproteinase domain-containing FT protein 17" FT /id="PRO_0000029089" FT TOPO_DOM 215..671 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 672..692 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 693..824 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT DOMAIN 223..474 FT /note="Peptidase M12B" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00276" FT DOMAIN 475..563 FT /note="Disintegrin" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00068" FT REGION 603..671 FT /note="Crambin-like" FT REGION 732..824 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 182..189 FT /note="Cysteine switch" FT /evidence="ECO:0000250" FT MOTIF 731..738 FT /note="SH3-binding" FT /evidence="ECO:0000255" FT MOTIF 741..748 FT /note="SH3-binding" FT /evidence="ECO:0000255" FT COMPBIAS 741..752 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 768..781 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 791..807 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 815..824 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 406 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00276, FT ECO:0000255|PROSITE-ProRule:PRU10095, FT ECO:0000269|PubMed:9520379" FT BINDING 184 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_note="catalytic" FT /note="in inhibited form" FT /evidence="ECO:0000250" FT BINDING 405 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:9520379" FT BINDING 409 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:9520379" FT BINDING 415 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:9520379" FT MOD_RES 735 FT /note="Phosphothreonine; by MAPK14" FT /evidence="ECO:0000269|PubMed:12058067, FT ECO:0000269|PubMed:20188673" FT MOD_RES 761 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 767 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9Z1K9" FT MOD_RES 791 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:17081983, FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163, FT ECO:0007744|PubMed:24275569" FT MOD_RES 819 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:12621058" FT CARBOHYD 103 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 157 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 174 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 264 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 452 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 498 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 539 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 551 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 594 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 225..333 FT /evidence="ECO:0000269|PubMed:9520379" FT DISULFID 365..469 FT /evidence="ECO:0000269|PubMed:9520379" FT DISULFID 423..453 FT /evidence="ECO:0000269|PubMed:9520379" FT DISULFID 534..555 FT /evidence="ECO:0000250" FT DISULFID 573..582 FT /evidence="ECO:0000250" FT DISULFID 578..591 FT /evidence="ECO:0000250" FT DISULFID 593..600 FT /evidence="ECO:0000250" FT VAR_SEQ 695..824 FT /note="Missing (in isoform B)" FT /evidence="ECO:0000303|PubMed:9034190" FT /id="VSP_005478" FT VARIANT 162 FT /note="K -> E (in dbSNP:rs34431503)" FT /id="VAR_051586" FT VARIANT 202 FT /note="R -> G (in dbSNP:rs2230818)" FT /id="VAR_051587" FT VARIANT 647 FT /note="D -> N (in HYPT16; pathogenic; results in decreased FT protein abundance due to increased ubiquitin-dependent FT proteasomal degradation; results in decreased activation of FT Notch signaling)" FT /evidence="ECO:0000269|PubMed:38771644" FT /id="VAR_091624" FT CONFLICT 109 FT /note="V -> A (in Ref. 3; AAC39721)" FT /evidence="ECO:0000305" FT CONFLICT 563 FT /note="D -> N (in Ref. 3; AAC39721)" FT /evidence="ECO:0000305" FT CONFLICT 801 FT /note="T -> A (in Ref. 3; AAC39721)" FT /evidence="ECO:0000305" FT CONFLICT 818 FT /note="D -> N (in Ref. 3; AAC39721)" FT /evidence="ECO:0000305" FT HELIX 33..38 FT /evidence="ECO:0007829|PDB:8SNL" FT STRAND 39..43 FT /evidence="ECO:0007829|PDB:8SNL" FT HELIX 47..49 FT /evidence="ECO:0007829|PDB:8SNL" FT STRAND 50..53 FT /evidence="ECO:0007829|PDB:8SNL" FT STRAND 65..73 FT /evidence="ECO:0007829|PDB:8SNL" FT STRAND 78..85 FT /evidence="ECO:0007829|PDB:8SNL" FT HELIX 87..89 FT /evidence="ECO:0007829|PDB:8SNL" FT STRAND 96..99 FT /evidence="ECO:0007829|PDB:8SNL" FT STRAND 104..107 FT /evidence="ECO:0007829|PDB:8SNL" FT HELIX 111..113 FT /evidence="ECO:0007829|PDB:8SNL" FT STRAND 114..119 FT /evidence="ECO:0007829|PDB:8SNL" FT STRAND 122..130 FT /evidence="ECO:0007829|PDB:8SNL" FT STRAND 137..141 FT /evidence="ECO:0007829|PDB:8SNL" FT STRAND 146..151 FT /evidence="ECO:0007829|PDB:8SNL" FT HELIX 152..155 FT /evidence="ECO:0007829|PDB:8SNL" FT STRAND 163..168 FT /evidence="ECO:0007829|PDB:8SNL" FT HELIX 169..171 FT /evidence="ECO:0007829|PDB:8SNL" FT STRAND 182..185 FT /evidence="ECO:0007829|PDB:8SNL" FT HELIX 191..193 FT /evidence="ECO:0007829|PDB:8SNL" FT HELIX 220..222 FT /evidence="ECO:0007829|PDB:3L0V" FT STRAND 224..231 FT /evidence="ECO:0007829|PDB:2DDF" FT HELIX 233..238 FT /evidence="ECO:0007829|PDB:2DDF" FT TURN 239..242 FT /evidence="ECO:0007829|PDB:3EDZ" FT HELIX 244..263 FT /evidence="ECO:0007829|PDB:2DDF" FT STRAND 269..271 FT /evidence="ECO:0007829|PDB:2DDF" FT STRAND 276..284 FT /evidence="ECO:0007829|PDB:2DDF" FT HELIX 288..290 FT /evidence="ECO:0007829|PDB:2DDF" FT STRAND 300..302 FT /evidence="ECO:0007829|PDB:2DDF" FT STRAND 309..311 FT /evidence="ECO:0007829|PDB:2DDF" FT HELIX 314..324 FT /evidence="ECO:0007829|PDB:2DDF" FT HELIX 326..329 FT /evidence="ECO:0007829|PDB:2DDF" FT STRAND 332..339 FT /evidence="ECO:0007829|PDB:2DDF" FT HELIX 344..346 FT /evidence="ECO:0007829|PDB:2DDF" FT STRAND 349..354 FT /evidence="ECO:0007829|PDB:2DDF" FT STRAND 355..357 FT /evidence="ECO:0007829|PDB:3O64" FT STRAND 363..365 FT /evidence="ECO:0007829|PDB:3O64" FT STRAND 368..371 FT /evidence="ECO:0007829|PDB:2DDF" FT TURN 372..375 FT /evidence="ECO:0007829|PDB:2DDF" FT STRAND 376..379 FT /evidence="ECO:0007829|PDB:2DDF" FT STRAND 382..389 FT /evidence="ECO:0007829|PDB:2DDF" FT HELIX 396..410 FT /evidence="ECO:0007829|PDB:2DDF" FT HELIX 415..417 FT /evidence="ECO:0007829|PDB:2DDF" FT STRAND 418..420 FT /evidence="ECO:0007829|PDB:3CKI" FT TURN 421..423 FT /evidence="ECO:0007829|PDB:2DDF" FT HELIX 427..429 FT /evidence="ECO:0007829|PDB:2DDF" FT STRAND 436..438 FT /evidence="ECO:0007829|PDB:3CKI" FT STRAND 442..444 FT /evidence="ECO:0007829|PDB:3LGP" FT TURN 445..448 FT /evidence="ECO:0007829|PDB:2DDF" FT HELIX 452..469 FT /evidence="ECO:0007829|PDB:2DDF" FT HELIX 472..474 FT /evidence="ECO:0007829|PDB:3EWJ" FT STRAND 480..482 FT /evidence="ECO:0007829|PDB:8SNN" FT STRAND 485..488 FT /evidence="ECO:0007829|PDB:8SNO" FT TURN 496..498 FT /evidence="ECO:0007829|PDB:8SNN" FT STRAND 500..502 FT /evidence="ECO:0007829|PDB:8SNN" FT STRAND 506..508 FT /evidence="ECO:0007829|PDB:8SNN" FT TURN 516..518 FT /evidence="ECO:0007829|PDB:8SNN" FT STRAND 520..523 FT /evidence="ECO:0007829|PDB:8SNL" FT STRAND 532..535 FT /evidence="ECO:0007829|PDB:8SNN" FT TURN 539..542 FT /evidence="ECO:0007829|PDB:8SNN" FT HELIX 555..558 FT /evidence="ECO:0007829|PDB:8SNN" FT STRAND 568..570 FT /evidence="ECO:0007829|PDB:8SNL" FT STRAND 572..574 FT /evidence="ECO:0007829|PDB:8SNN" FT STRAND 577..579 FT /evidence="ECO:0007829|PDB:8SNN" FT HELIX 581..584 FT /evidence="ECO:0007829|PDB:8SNN" FT STRAND 585..587 FT /evidence="ECO:0007829|PDB:8SNL" FT STRAND 589..591 FT /evidence="ECO:0007829|PDB:8SNN" FT HELIX 596..598 FT /evidence="ECO:0007829|PDB:8SNN" FT STRAND 603..605 FT /evidence="ECO:0007829|PDB:8SNN" FT STRAND 607..609 FT /evidence="ECO:0007829|PDB:8SNO" FT STRAND 611..613 FT /evidence="ECO:0007829|PDB:8SNN" FT TURN 616..619 FT /evidence="ECO:0007829|PDB:9E6K" FT STRAND 631..634 FT /evidence="ECO:0007829|PDB:8SNN" FT STRAND 637..639 FT /evidence="ECO:0007829|PDB:8SNL" FT STRAND 642..645 FT /evidence="ECO:0007829|PDB:8SNN" FT HELIX 648..657 FT /evidence="ECO:0007829|PDB:8SNN" FT HELIX 661..670 FT /evidence="ECO:0007829|PDB:8SNN" FT HELIX 672..702 FT /evidence="ECO:0007829|PDB:8SNN" FT STRAND 821..823 FT /evidence="ECO:0007829|PDB:8CQY" SQ SEQUENCE 824 AA; 93021 MW; 5B1032F6B88A837F CRC64; MRQSLLFLTS VVPFVLAPRP PDDPGFGPHQ RLEKLDSLLS DYDILSLSNI QQHSVRKRDL QTSTHVETLL TFSALKRHFK LYLTSSTERF SQNFKVVVVD GKNESEYTVK WQDFFTGHVV GEPDSRVLAH IRDDDVIIRI NTDGAEYNIE PLWRFVNDTK DKRMLVYKSE DIKNVSRLQS PKVCGYLKVD NEELLPKGLV DREPPEELVH RVKRRADPDP MKNTCKLLVV ADHRFYRYMG RGEESTTTNY LIELIDRVDD IYRNTSWDNA GFKGYGIQIE QIRILKSPQE VKPGEKHYNM AKSYPNEEKD AWDVKMLLEQ FSFDIAEEAS KVCLAHLFTY QDFDMGTLGL AYVGSPRANS HGGVCPKAYY SPVGKKNIYL NSGLTSTKNY GKTILTKEAD LVTTHELGHN FGAEHDPDGL AECAPNEDQG GKYVMYPIAV SGDHENNKMF SNCSKQSIYK TIESKAQECF QERSNKVCGN SRVDEGEECD PGIMYLNNDT CCNSDCTLKE GVQCSDRNSP CCKNCQFETA QKKCQEAINA TCKGVSYCTG NSSECPPPGN AEDDTVCLDL GKCKDGKCIP FCEREQQLES CACNETDNSC KVCCRDLSGR CVPYVDAEQK NLFLRKGKPC TVGFCDMNGK CEKRVQDVIE RFWDFIDQLS INTFGKFLAD NIVGSVLVFS LIFWIPFSIL VHCVDKKLDK QYESLSLFHP SNVEMLSSMD SASVRIIKPF PAPQTPGRLQ PAPVIPSAPA APKLDHQRMD TIQEDPSTDS HMDEDGFEKD PFPNSSTAAK SFEDLTDHPV TRSEKAASFK LQRQNRVDSK ETEC //