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Protein

Disintegrin and metalloproteinase domain-containing protein 17

Gene

Adam17

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Cleaves the membrane-bound precursor of TNF-alpha to its mature soluble form. Responsible for the proteolytical release of soluble JAM3 from endothelial cells surface (By similarity). 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. Acts as an activator of Notch pathway by mediating cleavage of Notch, generating the membrane-associated intermediate fragment called Notch extracellular truncation (NEXT). Plays a role in the proteolytic processing of ACE2 (By similarity).By similarity

Catalytic activityi

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 (TNF-alpha). Similarly cleaves other membrane-anchored, cell-surface proteins to 'shed' the extracellular domains.

Cofactori

Zn2+By similarityNote: Binds 1 zinc ion per subunit.By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Metal bindingi184Zinc; in inhibited formBy similarity1
Metal bindingi405Zinc; catalyticBy similarity1
Active sitei406PROSITE-ProRule annotation1
Metal bindingi409Zinc; catalyticBy similarity1
Metal bindingi415Zinc; catalyticBy similarity1

GO - Molecular functioni

  • metal ion binding Source: UniProtKB-KW
  • metalloendopeptidase activity Source: RGD
  • metallopeptidase activity Source: RGD
  • Notch binding Source: UniProtKB
  • SH3 domain binding Source: UniProtKB-KW

GO - Biological processi

  • membrane protein ectodomain proteolysis Source: RGD
  • negative regulation of apoptotic process Source: RGD
  • Notch receptor processing Source: UniProtKB
  • Notch signaling pathway Source: UniProtKB-KW
  • proteolysis Source: UniProtKB

Keywordsi

Molecular functionHydrolase, Metalloprotease, Protease
Biological processNotch signaling pathway
LigandMetal-binding, Zinc

Enzyme and pathway databases

BRENDAi3.4.24.86. 5301.

Protein family/group databases

MEROPSiM12.217.

Names & Taxonomyi

Protein namesi
Recommended name:
Disintegrin and metalloproteinase domain-containing protein 17 (EC:3.4.24.86)
Short name:
ADAM 17
Alternative name(s):
TNF-alpha convertase
TNF-alpha-converting enzyme
CD_antigen: CD156b
Gene namesi
Name:Adam17
Synonyms:Tace
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Unplaced

Organism-specific databases

RGDi620404. Adam17.

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini215 – 671ExtracellularSequence analysisAdd BLAST457
Transmembranei672 – 692HelicalSequence analysisAdd BLAST21
Topological domaini693 – 827CytoplasmicSequence analysisAdd BLAST135

Keywords - Cellular componenti

Membrane

Pathology & Biotechi

Chemistry databases

ChEMBLiCHEMBL2523.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 171 PublicationAdd BLAST17
PropeptideiPRO_000002909218 – 214By similarityAdd BLAST197
ChainiPRO_0000029093215 – 827Disintegrin and metalloproteinase domain-containing protein 17Add BLAST613

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi157N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi225 ↔ 333By similarity
Glycosylationi264N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi365 ↔ 469By similarity
Disulfide bondi423 ↔ 453By similarity
Glycosylationi452N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi498N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi534 ↔ 555By similarity
Glycosylationi539N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi551N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi573 ↔ 582By similarity
Disulfide bondi578 ↔ 591By similarity
Disulfide bondi593 ↔ 600By similarity
Glycosylationi606N-linked (GlcNAc...) asparagineSequence analysis1
Modified residuei735Phosphothreonine; by MAPK14By similarity1
Modified residuei764PhosphothreonineBy similarity1
Modified residuei770PhosphoserineCombined sources1
Modified residuei794PhosphoserineCombined sources1
Modified residuei822PhosphoserineBy similarity1

Post-translational modificationi

The precursor is cleaved by a furin endopeptidase.By similarity
Phosphorylated. Stimulation by growth factor or phorbol 12-myristate 13-acetate induces phosphorylation of Ser-822 but decreases phosphorylation of Ser-794. Phosphorylation at THR-735 by MAPK14 is required for ADAM17-mediated ectodomain shedding (By similarity).By similarity

Keywords - PTMi

Cleavage on pair of basic residues, Disulfide bond, Glycoprotein, Phosphoprotein, Zymogen

Proteomic databases

PaxDbiQ9Z1K9.
PRIDEiQ9Z1K9.

PTM databases

iPTMnetiQ9Z1K9.
PhosphoSitePlusiQ9Z1K9.

Interactioni

Subunit structurei

Interacts with MAD2L1, MAPK14 and MUC1.By similarity

GO - Molecular functioni

Protein-protein interaction databases

IntActiQ9Z1K9. 1 interactor.
STRINGi10116.ENSRNOP00000010648.

Chemistry databases

BindingDBiQ9Z1K9.

Structurei

3D structure databases

ProteinModelPortaliQ9Z1K9.
SMRiQ9Z1K9.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini223 – 474Peptidase M12BPROSITE-ProRule annotationAdd BLAST252
Domaini475 – 563DisintegrinPROSITE-ProRule annotationAdd BLAST89

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni603 – 671Crambin-likeAdd BLAST69

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi182 – 189Cysteine switchBy similarity8
Motifi731 – 738SH3-bindingSequence analysis8

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi96 – 99Poly-Val4
Compositional biasi564 – 602Cys-richAdd BLAST39

Domaini

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).By similarity
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.

Keywords - Domaini

SH3-binding, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG3658. Eukaryota.
ENOG410XQWB. LUCA.
HOGENOMiHOG000033797.
HOVERGENiHBG050457.
InParanoidiQ9Z1K9.
KOiK06059.
PhylomeDBiQ9Z1K9.

Family and domain databases

CDDicd04270. ZnMc_TACE_like. 1 hit.
Gene3Di3.40.390.10. 1 hit.
4.10.70.10. 1 hit.
InterProiView protein in InterPro
IPR034025. ADAM10_ADAM17.
IPR032029. ADAM17_MPD.
IPR001762. Disintegrin_dom.
IPR024079. MetalloPept_cat_dom.
IPR001590. Peptidase_M12B.
IPR002870. Peptidase_M12B_N.
PfamiView protein in Pfam
PF16698. ADAM17_MPD. 1 hit.
PF00200. Disintegrin. 1 hit.
PF01562. Pep_M12B_propep. 1 hit.
SMARTiView protein in SMART
SM00050. DISIN. 1 hit.
SUPFAMiSSF57552. SSF57552. 1 hit.
PROSITEiView protein in PROSITE
PS50215. ADAM_MEPRO. 1 hit.
PS50214. DISINTEGRIN_2. 1 hit.
PS00142. ZINC_PROTEASE. 1 hit.

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

Q9Z1K9-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MRQRLLFLTT LVPFVLAPRP PEEPGSGSHL RLEKLDSLLS DYDILSLSNI
60 70 80 90 100
QQHSIRKRDL QSATHLETLL TFSALKRHFK LYLTSSTERF SQNLRVVVVD
110 120 130 140 150
GKEESEYSVK WQDFFSGHVV GEPDSRVLAH IGDDDVTVRI NTDGAEYNIE
160 170 180 190 200
PLWRFVNDTK DKRMLVYKSE DIKDFSRLQS PKVCGYLNAD SEELLPKGLI
210 220 230 240 250
DREPSEEFVR RVKRRAEPNP LKNTCKLLVV ADHRFYKYMG RGEESTTTNY
260 270 280 290 300
LIELIDRVDD IYRNTSWDNA GFKGYGVQIE QIRILKSPQE VKPGERHFNM
310 320 330 340 350
AKSFPNEEKD AWDVKMLLEQ FSLDIAEEAS KVCLAHLFTY QDFDMGTLGL
360 370 380 390 400
AYVGSPRANS HGGVCPKAYY NPGVKKNIYL NSGLTSTKNY GKTILTKEAD
410 420 430 440 450
LVTTHELGHN FGAEHDPDGL AECAPNEDQG GKYVMYPIAV SGDHENNKMF
460 470 480 490 500
SNCSKQSIYK TIESKAQECF QERSNKVCGN SRVDEGEECD PGIMYLNNDT
510 520 530 540 550
CCNSDCTLKP GVQCSDRNSP CCKNCQFETA QKKCQEAINA TCKGVSYCTG
560 570 580 590 600
NSSECPPPGD AEDDTVCLDL GKCKAGKCIP FCKREQELES CACADTDNSC
610 620 630 640 650
KVCCRNLSGP CVPYVDAEQK NLFLRKGKPC TVGFCDMNGK CEKRVQDVIE
660 670 680 690 700
RFWDFIDQLS INTFGKFLAD NIVGSVLVFS LIFWIPFSIL VHCVDKKLDK
710 720 730 740 750
QYESLSLFHH SNIEMLSSMD SASVRIIKPF PAPQTPGRLQ ALQPAAMMPP
760 770 780 790 800
VSAAPKLDHQ RMDTIQEDPS TDSHVDDDGF EKDPFPNSSA AAKSFEDLTD
810 820
HPVTRSEKAA SFKLQRQSRV DSKETEC
Length:827
Mass (Da):93,017
Last modified:May 1, 1999 - v1
Checksum:iEF82239C067F2AFF
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AJ012603 mRNA. Translation: CAA10072.1.
RefSeqiNP_064702.1. NM_020306.2.
UniGeneiRn.144585.

Genome annotation databases

GeneIDi57027.
KEGGirno:57027.

Similar proteinsi

Entry informationi

Entry nameiADA17_RAT
AccessioniPrimary (citable) accession number: Q9Z1K9
Entry historyiIntegrated into UniProtKB/Swiss-Prot: June 20, 2001
Last sequence update: May 1, 1999
Last modified: August 30, 2017
This is version 134 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome