ADA17_RAT
ID ADA17_RAT Reviewed; 827 AA.
AC Q9Z1K9;
DT 20-JUN-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-1999, sequence version 1.
DT 03-AUG-2022, entry version 158.
DE RecName: Full=Disintegrin and metalloproteinase domain-containing protein 17;
DE Short=ADAM 17;
DE EC=3.4.24.86 {ECO:0000250|UniProtKB:P78536};
DE AltName: Full=TNF-alpha convertase;
DE AltName: Full=TNF-alpha-converting enzyme;
DE AltName: CD_antigen=CD156b;
DE Flags: Precursor;
GN Name=Adam17; Synonyms=Tace;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Testis;
RA Hall L., Beaumont A.J., Jury J.A., Frayne J.;
RT "Sequence analysis of rat TNF-alpha converting enzyme (TACE) cDNA.";
RL Submitted (NOV-1998) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-770 AND SER-794, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
RN [3]
RP CLEAVAGE OF SIGNAL PEPTIDE AFTER ALA-17, AND IDENTIFICATION BY MASS
RP SPECTROMETRY.
RX PubMed=26479776; DOI=10.1021/acs.jproteome.5b00820;
RA Tsuchiya T., Osaki T., Minamino N., Sasaki K.;
RT "Peptidomics for studying limited proteolysis.";
RL J. Proteome Res. 14:4921-4931(2015).
CC -!- FUNCTION: Cleaves the membrane-bound precursor of TNF-alpha to its
CC mature soluble form. Responsible for the proteolytical release of
CC soluble JAM3 from endothelial cells surface. Responsible for the
CC proteolytic release of several other cell-surface proteins, including
CC p75 TNF-receptor, interleukin 1 receptor type II, p55 TNF-receptor,
CC transforming growth factor-alpha, L-selectin, growth hormone receptor,
CC MUC1 and the amyloid precursor protein. Acts as an activator of Notch
CC pathway by mediating cleavage of Notch, generating the membrane-
CC associated intermediate fragment called Notch extracellular truncation
CC (NEXT). Plays a role in the proteolytic processing of ACE2 (By
CC similarity). Plays a role in hemostasis through shedding of GP1BA, the
CC platelet glycoprotein Ib alpha chain (By similarity). Mediates the
CC proteolytic cleavage of LAG3, leading to release the secreted form of
CC LAG3 (By similarity). Mediates the proteolytic cleavage of IL6R,
CC leading to the release of secreted form of IL6R (By similarity).
CC Mediates the proteolytic cleavage and shedding of FCGR3A upon NK cell
CC stimulation, a mechanism that allows for increased NK cell motility and
CC detachment from opsonized target cells. {ECO:0000250|UniProtKB:P78536,
CC ECO:0000250|UniProtKB:Q9Z0F8}.
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:0000250|UniProtKB:P78536};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000250|UniProtKB:P78536};
CC Note=Binds 1 zinc ion per subunit. {ECO:0000250|UniProtKB:P78536};
CC -!- SUBUNIT: Interacts with MAD2L1, MAPK14 and MUC1. Interacts with
CC iRhom1/RHBDF1 and iRhom2/RHBDF2. Interacts with FRMD8 via its
CC interaction with iRhom1/RHBDF1 and iRhom2/RHBDF2.
CC {ECO:0000250|UniProtKB:P78536}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Single-pass type I
CC membrane protein {ECO:0000255}.
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-822 but decreases
CC phosphorylation of Ser-794. Phosphorylation at THR-735 by MAPK14 is
CC required for ADAM17-mediated ectodomain shedding (By similarity).
CC {ECO:0000250|UniProtKB:P78536}.
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DR EMBL; AJ012603; CAA10072.1; -; mRNA.
DR RefSeq; NP_064702.1; NM_020306.2.
DR AlphaFoldDB; Q9Z1K9; -.
DR SMR; Q9Z1K9; -.
DR BioGRID; 248605; 1.
DR IntAct; Q9Z1K9; 1.
DR STRING; 10116.ENSRNOP00000010648; -.
DR BindingDB; Q9Z1K9; -.
DR ChEMBL; CHEMBL2523; -.
DR MEROPS; M12.217; -.
DR GlyGen; Q9Z1K9; 7 sites.
DR iPTMnet; Q9Z1K9; -.
DR PhosphoSitePlus; Q9Z1K9; -.
DR PaxDb; Q9Z1K9; -.
DR GeneID; 57027; -.
DR KEGG; rno:57027; -.
DR CTD; 6868; -.
DR RGD; 620404; Adam17.
DR eggNOG; KOG3658; Eukaryota.
DR InParanoid; Q9Z1K9; -.
DR OrthoDB; 162519at2759; -.
DR PhylomeDB; Q9Z1K9; -.
DR BRENDA; 3.4.24.86; 5301.
DR Reactome; R-RNO-193692; Regulated proteolysis of p75NTR.
DR Reactome; R-RNO-75893; TNF signaling.
DR PRO; PR:Q9Z1K9; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0015629; C:actin cytoskeleton; ISO:RGD.
DR GO; GO:0045177; C:apical part of cell; IDA:RGD.
DR GO; GO:0016324; C:apical plasma membrane; ISO:RGD.
DR GO; GO:0009986; C:cell surface; IDA:RGD.
DR GO; GO:0005737; C:cytoplasm; ISO:RGD.
DR GO; GO:0031410; C:cytoplasmic vesicle; IDA:RGD.
DR GO; GO:0005887; C:integral component of plasma membrane; ISO:RGD.
DR GO; GO:0016020; C:membrane; ISO:RGD.
DR GO; GO:0045121; C:membrane raft; ISO:RGD.
DR GO; GO:0005886; C:plasma membrane; IDA:RGD.
DR GO; GO:0004175; F:endopeptidase activity; ISS:UniProtKB.
DR GO; GO:0005178; F:integrin binding; ISO:RGD.
DR GO; GO:0005138; F:interleukin-6 receptor binding; ISO:RGD.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0070573; F:metallodipeptidase activity; ISO:RGD.
DR GO; GO:0004222; F:metalloendopeptidase activity; ISS:UniProtKB.
DR GO; GO:1902945; F:metalloendopeptidase activity involved in amyloid precursor protein catabolic process; ISO:RGD.
DR GO; GO:0008237; F:metallopeptidase activity; ISO:RGD.
DR GO; GO:0005112; F:Notch binding; ISS:UniProtKB.
DR GO; GO:0030165; F:PDZ domain binding; ISO:RGD.
DR GO; GO:0017124; F:SH3 domain binding; IEA:UniProtKB-KW.
DR GO; GO:0042987; P:amyloid precursor protein catabolic process; ISO:RGD.
DR GO; GO:0030183; P:B cell differentiation; ISO:RGD.
DR GO; GO:0007155; P:cell adhesion; ISO:RGD.
DR GO; GO:0033627; P:cell adhesion mediated by integrin; ISO:RGD.
DR GO; GO:0048870; P:cell motility; ISO:RGD.
DR GO; GO:0071403; P:cellular response to high density lipoprotein particle stimulus; ISO:RGD.
DR GO; GO:0050830; P:defense response to Gram-positive bacterium; ISO:RGD.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; ISO:RGD.
DR GO; GO:0002467; P:germinal center formation; ISO:RGD.
DR GO; GO:0006509; P:membrane protein ectodomain proteolysis; IMP:RGD.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IDA:RGD.
DR GO; GO:0120163; P:negative regulation of cold-induced thermogenesis; ISS:YuBioLab.
DR GO; GO:0010977; P:negative regulation of neuron projection development; ISO:RGD.
DR GO; GO:0030512; P:negative regulation of transforming growth factor beta receptor signaling pathway; ISO:RGD.
DR GO; GO:0007220; P:Notch receptor processing; ISS:UniProtKB.
DR GO; GO:0007219; P:Notch signaling pathway; IBA:GO_Central.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IMP:RGD.
DR GO; GO:0043536; P:positive regulation of blood vessel endothelial cell migration; ISO:RGD.
DR GO; GO:0030307; P:positive regulation of cell growth; ISO:RGD.
DR GO; GO:0030335; P:positive regulation of cell migration; ISO:RGD.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; ISO:RGD.
DR GO; GO:0032722; P:positive regulation of chemokine production; ISO:RGD.
DR GO; GO:0045737; P:positive regulation of cyclin-dependent protein serine/threonine kinase activity; ISO:RGD.
DR GO; GO:0045741; P:positive regulation of epidermal growth factor-activated receptor activity; ISO:RGD.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IMP:RGD.
DR GO; GO:1900087; P:positive regulation of G1/S transition of mitotic cell cycle; ISO:RGD.
DR GO; GO:0010976; P:positive regulation of neuron projection development; IMP:RGD.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; ISO:RGD.
DR GO; GO:0010820; P:positive regulation of T cell chemotaxis; ISO:RGD.
DR GO; GO:0030511; P:positive regulation of transforming growth factor beta receptor signaling pathway; ISO:RGD.
DR GO; GO:1903265; P:positive regulation of tumor necrosis factor-mediated signaling pathway; ISO:RGD.
DR GO; GO:1905564; P:positive regulation of vascular endothelial cell proliferation; ISO:RGD.
DR GO; GO:0002532; P:production of molecular mediator involved in inflammatory response; ISO:RGD.
DR GO; GO:0016485; P:protein processing; ISO:RGD.
DR GO; GO:0006508; P:proteolysis; ISS:UniProtKB.
DR GO; GO:0035624; P:receptor transactivation; IMP:RGD.
DR GO; GO:0048679; P:regulation of axon regeneration; ISO:RGD.
DR GO; GO:0033025; P:regulation of mast cell apoptotic process; ISO:RGD.
DR GO; GO:2001222; P:regulation of neuron migration; ISO:RGD.
DR GO; GO:0097327; P:response to antineoplastic agent; IEP:RGD.
DR GO; GO:1990910; P:response to hypobaric hypoxia; IEP:RGD.
DR GO; GO:0001666; P:response to hypoxia; ISO:RGD.
DR GO; GO:0032496; P:response to lipopolysaccharide; ISO:RGD.
DR GO; GO:0009410; P:response to xenobiotic stimulus; ISO:RGD.
DR GO; GO:0140448; P:signaling receptor ligand precursor processing; ISO:RGD.
DR GO; GO:0007283; P:spermatogenesis; IEP:RGD.
DR GO; GO:0048536; P:spleen development; ISO:RGD.
DR GO; GO:0033077; P:T cell differentiation in thymus; ISO:RGD.
DR GO; GO:0035313; P:wound healing, spreading of epidermal cells; ISO:RGD.
DR CDD; cd14246; ADAM17_MPD; 1.
DR CDD; cd04270; ZnMc_TACE_like; 1.
DR Gene3D; 3.40.390.10; -; 1.
DR Gene3D; 4.10.70.10; -; 1.
DR InterPro; IPR034025; ADAM10_ADAM17.
DR InterPro; IPR032029; ADAM17_MPD.
DR InterPro; IPR001762; Disintegrin_dom.
DR InterPro; IPR036436; Disintegrin_dom_sf.
DR InterPro; IPR024079; MetalloPept_cat_dom_sf.
DR InterPro; IPR001590; Peptidase_M12B.
DR InterPro; IPR002870; Peptidase_M12B_N.
DR Pfam; PF16698; ADAM17_MPD; 1.
DR Pfam; PF00200; Disintegrin; 1.
DR Pfam; PF01562; Pep_M12B_propep; 1.
DR SMART; SM00050; DISIN; 1.
DR SUPFAM; SSF57552; SSF57552; 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 Cleavage on pair of basic residues; Disulfide bond; Glycoprotein;
KW Hydrolase; Membrane; Metal-binding; Metalloprotease;
KW Notch signaling pathway; Phosphoprotein; Protease; Reference proteome;
KW SH3-binding; Signal; Transmembrane; Transmembrane helix; Zinc; Zymogen.
FT SIGNAL 1..17
FT /evidence="ECO:0000269|PubMed:26479776"
FT PROPEP 18..214
FT /evidence="ECO:0000250|UniProtKB:P78536"
FT /id="PRO_0000029092"
FT CHAIN 215..827
FT /note="Disintegrin and metalloproteinase domain-containing
FT protein 17"
FT /id="PRO_0000029093"
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..827
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 766..827
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 COMPBIAS 766..783
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 798..827
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 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:0000250|UniProtKB:P78536"
FT BINDING 409
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:P78536"
FT BINDING 415
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:P78536"
FT MOD_RES 735
FT /note="Phosphothreonine; by MAPK14"
FT /evidence="ECO:0000250|UniProtKB:P78536"
FT MOD_RES 764
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P78536"
FT MOD_RES 770
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 794
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 822
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P78536"
FT CARBOHYD 157
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 606
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 225..333
FT /evidence="ECO:0000250|UniProtKB:P78536"
FT DISULFID 365..469
FT /evidence="ECO:0000250|UniProtKB:P78536"
FT DISULFID 423..453
FT /evidence="ECO:0000250|UniProtKB:P78536"
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"
SQ SEQUENCE 827 AA; 93017 MW; EF82239C067F2AFF CRC64;
MRQRLLFLTT LVPFVLAPRP PEEPGSGSHL RLEKLDSLLS DYDILSLSNI QQHSIRKRDL
QSATHLETLL TFSALKRHFK LYLTSSTERF SQNLRVVVVD GKEESEYSVK WQDFFSGHVV
GEPDSRVLAH IGDDDVTVRI NTDGAEYNIE PLWRFVNDTK DKRMLVYKSE DIKDFSRLQS
PKVCGYLNAD SEELLPKGLI DREPSEEFVR RVKRRAEPNP LKNTCKLLVV ADHRFYKYMG
RGEESTTTNY LIELIDRVDD IYRNTSWDNA GFKGYGVQIE QIRILKSPQE VKPGERHFNM
AKSFPNEEKD AWDVKMLLEQ FSLDIAEEAS KVCLAHLFTY QDFDMGTLGL AYVGSPRANS
HGGVCPKAYY NPGVKKNIYL NSGLTSTKNY GKTILTKEAD LVTTHELGHN FGAEHDPDGL
AECAPNEDQG GKYVMYPIAV SGDHENNKMF SNCSKQSIYK TIESKAQECF QERSNKVCGN
SRVDEGEECD PGIMYLNNDT CCNSDCTLKP GVQCSDRNSP CCKNCQFETA QKKCQEAINA
TCKGVSYCTG NSSECPPPGD AEDDTVCLDL GKCKAGKCIP FCKREQELES CACADTDNSC
KVCCRNLSGP CVPYVDAEQK NLFLRKGKPC TVGFCDMNGK CEKRVQDVIE RFWDFIDQLS
INTFGKFLAD NIVGSVLVFS LIFWIPFSIL VHCVDKKLDK QYESLSLFHH SNIEMLSSMD
SASVRIIKPF PAPQTPGRLQ ALQPAAMMPP VSAAPKLDHQ RMDTIQEDPS TDSHVDDDGF
EKDPFPNSSA AAKSFEDLTD HPVTRSEKAA SFKLQRQSRV DSKETEC
