Reviewed, UniProtKB/Swiss-Prot Q9Z0F8 (ADA17_MOUSE)

Names and origin

Protein names

Recommended name:
    Disintegrin and metalloproteinase domain-containing protein 17
      Short name=ADAM 17
    EC=3.4.24.86
Alternative name(s):
    TNF-alpha-converting enzyme
    TNF-alpha convertase
    CD_antigen=CD156b

Gene names

Name:	Adam17
Synonyms:	Tace

Organism

Mus musculus (Mouse)

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus

Protein attributes

Sequence length	827 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Cleaves the membrane-bound precursor of TNF-alpha to its mature soluble form. 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. Also involved in the activation of Notch pathway By similarity. Ref.4
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 (TNF-alpha). Similarly cleaves other membrane-anchored, cell-surface proteins to 'shed' the extracellular domains.
Cofactor	Binds 1 zinc ion per subunit By similarity.
Enzyme regulation	Inhibited by metalloproteinase inhibitor 3 (TIMP-3), but not by TIMP-1, TIMP-2 and TIMP-4.
Subunit structure	Interacts with MAD2L1 and MUC1 By similarity.
Subcellular location	Isoform Long: Cell membrane; Single-pass type I membrane protein. Isoform Short: Secreted.
Tissue specificity	Ubiquitously expressed. Expressed at highest levels in heart, liver, skeletal muscle, kidney and testes. Expressed at lower levels in brain, spleen and lung.
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. 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.
Post-translational modification	The precursor is cleaved by a furin endopeptidase By similarity. Ref.4 Phosphorylated. Stimulation by growth factor or phorbol 12-myristate 13-acetate induces phosphorylation of Ser-822 but decreases phosphorylation of Ser-794 By similarity. Ref.8 Ref.9
Sequence similarities	Contains 1 disintegrin domain. Contains 1 peptidase M12B domain.

Ontologies

Keywords
Biological process	Notch signaling pathway
Cellular component	Cell membrane Membrane Secreted
Coding sequence diversity	Alternative splicing
Domain	SH3-binding Signal Transmembrane
Ligand	Metal-binding Zinc
Molecular function	Hydrolase Metalloprotease Protease
PTM	Cleavage on pair of basic residues Disulfide bond Glycoprotein Phosphoprotein Zymogen
Gene Ontology (GO)
Biological process	B cell differentiation Inferred from mutant phenotype. Source: UniProtKB Notch signaling pathway Inferred from electronic annotation. Source: UniProtKB-KW PMA-inducible membrane protein ectodomain proteolysis Inferred from direct assay. Source: UniProtKB T cell differentiation in the thymus Inferred from mutant phenotype. Source: UniProtKB cell motility Inferred from mutant phenotype. Source: UniProtKB germinal center formation Inferred from mutant phenotype. Source: UniProtKB positive regulation of cellular component movement Inferred from mutant phenotype. Source: UniProtKB positive regulation of transforming growth factor beta receptor signaling pathway Inferred from mutant phenotype. Source: UniProtKB regulation of mast cell apoptosis Inferred from mutant phenotype. Source: UniProtKB response to drug Inferred from mutant phenotype. Source: UniProtKB spleen development Inferred from mutant phenotype. Source: UniProtKB
Cellular component	cytoplasm Inferred from direct assay. Source: MGI extracellular region Inferred from electronic annotation. Source: UniProtKB-KW integral to membrane Inferred from electronic annotation. Source: UniProtKB-SubCell plasma membrane Inferred from Experiment. Source: Reactome
Molecular function	SH3 domain binding Inferred from electronic annotation. Source: UniProtKB-KW metalloendopeptidase activity Inferred from electronic annotation. Source: InterPro zinc ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform Long (identifier: Q9Z0F8-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform Short (identifier: Q9Z0F8-2)

The sequence of this isoform differs from the canonical sequence as follows:
     639-655: GKCEKRVQDVIERFWDF → CDFFSPYRANVRNEYRT
     656-827: Missing.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 17	17	Potential
	Propeptide	18 – 214	197	By similarity		PRO_0000029090
	Chain	215 – 827	613	Disintegrin and metalloproteinase domain-containing protein 17		PRO_0000029091
Regions
	Topological domain	215 – 671	457	Extracellular Potential
	Transmembrane	672 – 692	21	Potential
	Topological domain	693 – 827	135	Cytoplasmic Potential
	Domain	223 – 474	252	Peptidase M12B
	Domain	475 – 563	89	Disintegrin
	Region	603 – 671	69	Crambin-like
	Motif	182 – 189	8	Cysteine switch By similarity
	Motif	731 – 738	8	SH3-binding Potential
	Compositional bias	96 – 99	4	Poly-Val
	Compositional bias	564 – 602	39	Cys-rich
Sites
	Active site	406	1	By similarity
	Metal binding	184	1	Zinc; in inhibited form By similarity
	Metal binding	405	1	Zinc; catalytic By similarity
	Metal binding	409	1	Zinc; catalytic By similarity
	Metal binding	415	1	Zinc; catalytic By similarity
Amino acid modifications
	Modified residue	379	1	Phosphotyrosine By similarity
	Modified residue	382	1	Phosphoserine By similarity
	Modified residue	735	1	Phosphothreonine; by MAPK By similarity
	Modified residue	794	1	Phosphoserine Ref.8 Ref.9
	Modified residue	822	1	Phosphoserine By similarity
	Glycosylation	157	1	N-linked (GlcNAc...) Potential
	Glycosylation	264	1	N-linked (GlcNAc...) Potential
	Glycosylation	452	1	N-linked (GlcNAc...) Potential
	Glycosylation	498	1	N-linked (GlcNAc...) Potential
	Glycosylation	539	1	N-linked (GlcNAc...) Potential
	Glycosylation	551	1	N-linked (GlcNAc...) Potential
	Glycosylation	606	1	N-linked (GlcNAc...) Potential
	Disulfide bond	225 ↔ 333		By similarity
	Disulfide bond	365 ↔ 469		By similarity
	Disulfide bond	423 ↔ 453		By similarity
	Disulfide bond	534 ↔ 555		By similarity
	Disulfide bond	573 ↔ 582		By similarity
	Disulfide bond	578 ↔ 591		By similarity
	Disulfide bond	593 ↔ 600		By similarity
Natural variations
	Alternative sequence	639 – 655	17	GKCEK…RFWDF → CDFFSPYRANVRNEYRT in isoform Short.		VSP_005479
	Alternative sequence	656 – 827	172	Missing in isoform Short.		VSP_005480
Experimental info
	Sequence conflict	3 – 4	2	RR → QS in CAA07480. Ref.2
	Sequence conflict	7	1	I → F in CAA07480. Ref.2
	Sequence conflict	28	1	A → S in AAD09627. Ref.1
	Sequence conflict	28	1	A → S in AAC62934. Ref.1
	Sequence conflict	28	1	A → S in AAD09628. Ref.1
	Sequence conflict	149	1	I → V in AAD09627. Ref.1
	Sequence conflict	149	1	I → V in AAC62934. Ref.1
	Sequence conflict	149	1	I → V in AAD09628. Ref.1
	Sequence conflict	594	1	V → I in AAD09627. Ref.1
	Sequence conflict	594	1	V → I in AAC62934. Ref.1
	Sequence conflict	594	1	V → I in AAD09628. Ref.1
	Sequence conflict	752	1	S → P in AAD09627. Ref.1
	Sequence conflict	752	1	S → P in AAC62934. Ref.1
	Sequence conflict	775	1	V → A in AAD09627. Ref.1
	Sequence conflict	775	1	V → A in AAC62934. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Isoform Long [UniParc]. Last modified June 20, 2001. Version 2. Checksum: 79751D0F1B52DC01	FASTA	827	93,073
	10 20 30 40 50 60 MRRRLLILTT LVPFVLAPRP PEEAGSGAHP RLEKLDSLLS DYDILSLANI QQHSIRKRDL 70 80 90 100 110 120 QSATHLETLL TFSALKRHFK LYLTSSTERF SQNLRVVVVD GKEESEYSVK WQDFFSGHVV 130 140 150 160 170 180 GEPDSRVLAH IGDDDVTVRI NTDGAEYNIE PLWRFVNDTK DKRMLVYKSE DIKDFSRLQS 190 200 210 220 230 240 PKVCGYLNAD SEELLPKGLI DREPSEEFVR RVKRRAEPNP LKNTCKLLVV ADHRFYKYMG 250 260 270 280 290 300 RGEESTTTNY LIELIDRVDD IYRNTSWDNA GFKGYGVQIE QIRILKSPQE VKPGERHFNM 310 320 330 340 350 360 AKSFPNEEKD AWDVKMLLEQ FSFDIAEEAS KVCLAHLFTY QDFDMGTLGL AYVGSPRANS 370 380 390 400 410 420 HGGVCPKAYY NPTVKKNIYL NSGLTSTKNY GKTILTKEAD LVTTHELGHN FGAEHDPDGL 430 440 450 460 470 480 AECAPNEDQG GKYVMYPIAV SGDHENNKMF SNCSKQSIYK TIESKAQECF QERSNKVCGN 490 500 510 520 530 540 SRVDEGEECD PGIMYLNNDT CCNSDCTLKP GVQCSDRNSP CCKNCQFETA QKKCQEAINA 550 560 570 580 590 600 TCKGVSYCTG NSSECPPPGD AEDDTVCLDL GKCKAGKCIP FCKREQELES CACVDTDNSC 610 620 630 640 650 660 KVCCRNLSGP CVPYVDAEQK NLFLRKGKPC TVGFCDMNGK CEKRVQDVIE RFWDFIDQLS 670 680 690 700 710 720 INTFGKFLAD NIVGSVLVFS LIFWIPFSIL VHCVDKKLDK QYESLSLFHH SNIEMLSSMD 730 740 750 760 770 780 SASVRIIKPF PAPQTPGRLQ ALQPAAMMPP VSAAPKLDHQ RMDTIQEDPS TDSHVDDDGF 790 800 810 820 EKDPFPNSST AAKSFEDLTD HPVTRSEKAA SFKLQRQSRV DSKETEC
	Isoform Short. Checksum: AD2AB0C0D6510507	FASTA	655	73,883
	10 20 30 40 50 60 MRRRLLILTT LVPFVLAPRP PEEAGSGAHP RLEKLDSLLS DYDILSLANI QQHSIRKRDL 70 80 90 100 110 120 QSATHLETLL TFSALKRHFK LYLTSSTERF SQNLRVVVVD GKEESEYSVK WQDFFSGHVV 130 140 150 160 170 180 GEPDSRVLAH IGDDDVTVRI NTDGAEYNIE PLWRFVNDTK DKRMLVYKSE DIKDFSRLQS 190 200 210 220 230 240 PKVCGYLNAD SEELLPKGLI DREPSEEFVR RVKRRAEPNP LKNTCKLLVV ADHRFYKYMG 250 260 270 280 290 300 RGEESTTTNY LIELIDRVDD IYRNTSWDNA GFKGYGVQIE QIRILKSPQE VKPGERHFNM 310 320 330 340 350 360 AKSFPNEEKD AWDVKMLLEQ FSFDIAEEAS KVCLAHLFTY QDFDMGTLGL AYVGSPRANS 370 380 390 400 410 420 HGGVCPKAYY NPTVKKNIYL NSGLTSTKNY GKTILTKEAD LVTTHELGHN FGAEHDPDGL 430 440 450 460 470 480 AECAPNEDQG GKYVMYPIAV SGDHENNKMF SNCSKQSIYK TIESKAQECF QERSNKVCGN 490 500 510 520 530 540 SRVDEGEECD PGIMYLNNDT CCNSDCTLKP GVQCSDRNSP CCKNCQFETA QKKCQEAINA 550 560 570 580 590 600 TCKGVSYCTG NSSECPPPGD AEDDTVCLDL GKCKAGKCIP FCKREQELES CACVDTDNSC 610 620 630 640 650 KVCCRNLSGP CVPYVDAEQK NLFLRKGKPC TVGFCDMNCD FFSPYRANVR NEYRT

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Characterization of the cDNA and gene for mouse tumour necrosis factor alpha converting enzyme (TACE/ADAM17) and its location to mouse chromosome 12 and human chromosome 2p25." Cerretti D.P., Poindexter K., Castner B.J., Means G., Copeland N.G., Gilbert D.J., Jenkins N.A., Black R.A., Nelson N. Cytokine 11:541-551(1999) [PubMed: 10433800] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS LONG AND SHORT).
[2]	"TNF-alpha converting enzyme (TACE) is inhibited by TIMP-3." Amour A., Slocombe P.M., Webster A., Butler M., Knight C.G., Smith B.J., Stephens P.E., Shelley C., Hutton M., Knauper V., Docherty A.J., Murphy G. FEBS Lett. 435:39-44(1998) [PubMed: 9755855] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG).
[3]	"cDNA cloning of mouse tumor necrosis factor-alpha converting enzyme (TACE) and partial analysis of its promoter." Mizui Y., Yamazaki K., Sagane K., Tanaka I. Gene 233:67-74(1999) [PubMed: 10375622] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG).
[4]	"Tumor necrosis factor-alpha converting enzyme (TACE) is a growth hormone binding protein (GHBP) sheddase: the metalloprotease TACE/ADAM-17 is critical for (PMA-induced) GH receptor proteolysis and GHBP generation." Zhang Y., Jiang J., Black R.A., Baumann G., Frank S.J. Endocrinology 141:4342-4348(2000) [PubMed: 11108241] [Abstract] Cited for: FUNCTION IN PROCESSING OF GROWTH HORMONE RECEPTOR.
[5]	"Isolation of murine TNF-alpha converting enzyme." Cerretti D.P. Submitted (SEP-1996) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM SHORT).
[6]	"Functional analysis of the domain structure of tumor necrosis factor-alpha converting enzyme." Reddy P., Slack J.L., Davis R., Cerretti D.P., Kozlosky C.J., Blanton R.A., Shows D., Peschon J.J., Black R.A. J. Biol. Chem. 275:14608-14614(2000) [PubMed: 10799547] [Abstract] Cited for: CHARACTERIZATION.
[7]	"A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE." Brou C., Logeat F., Gupta N., Bessia C., LeBail O., Doedens J.R., Cumano A., Roux P., Black R.A., Israel A. Mol. Cell 5:207-216(2000) [PubMed: 10882063] [Abstract] Cited for: CHARACTERIZATION.
[8]	"Solid tumor proteome and phosphoproteome analysis by high resolution mass spectrometry." Zanivan S., Gnad F., Wickstroem S.A., Geiger T., Macek B., Cox J., Faessler R., Mann M. J. Proteome Res. 7:5314-5326(2008) [PubMed: 18973353] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-794, MASS SPECTROMETRY.
[9]	"The phagosomal proteome in interferon-gamma-activated macrophages." Trost M., English L., Lemieux S., Courcelles M., Desjardins M., Thibault P. Immunity 30:143-154(2009) [PubMed: 19144319] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-794, MASS SPECTROMETRY. Tissue: Macrophage.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	U69613 mRNA. Translation: AAD09627.1. AF056359 , AF056345, AF056346, AF056347, AF056348, AF056349, AF056350, AF056351, AF056352, AF056353, AF056354, AF056355, AF056356, AF056357, AF056358 Genomic DNA. Translation: AAC62934.1. AJ007365 mRNA. Translation: CAA07480.1. AB021709 mRNA. Translation: BAA78578.1. U69614 mRNA. Translation: AAD09628.1.
IPI	IPI00381630. IPI00762180.
UniGene	Mm.27681
3D structure databases
SMR	Q9Z0F8. Positions 216-477, 225-581, 506-642.
ModBase	Search...
Protein-protein interaction databases
STRING	Q9Z0F8.
Protein family/group databases
MEROPS	M12.217.
PTM databases
PhosphoSite	Q9Z0F8.
Proteomic databases
PRIDE	Q9Z0F8.
Genome annotation databases
Ensembl	ENSMUST00000064536; ENSMUSP00000067953; ENSMUSG00000052593; Mus musculus. [Genome view]
Organism-specific databases
MGI	MGI:1096335. Adam17.
Phylogenomic databases
eggNOG	roNOG04504.
HOVERGEN	Q9Z0F8.
Enzyme and pathway databases
BRENDA	3.4.24.86. 244.
Gene expression databases
ArrayExpress	Q9Z0F8.
Bgee	Q9Z0F8.
CleanEx	MM_ADAM17.
Genevestigator	Q9Z0F8.
GermOnline	ENSMUSG00000052593. Mus musculus.
Family and domain databases
InterPro	IPR001762. Blood-coag_inhib_Disintegrin. IPR001590. Peptidase_M12B. IPR002870. Peptidase_M12B_N. [Graphical view]
Pfam	PF00200. Disintegrin. 1 hit. PF01562. Pep_M12B_propep. 1 hit. PF01421. Reprolysin. 1 hit. [Graphical view]
SMART	SM00050. DISIN. 1 hit. [Graphical view]
PROSITE	PS50215. ADAM_MEPRO. 1 hit. PS00546. CYSTEINE_SWITCH. False negative. PS00427. DISINTEGRIN_1. False negative. PS50214. DISINTEGRIN_2. 1 hit. PS00142. ZINC_PROTEASE. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
SOURCE	Search...

Entry information

Entry name

ADA17_MOUSE

Accession

Primary (citable) accession number: Q9Z0F8
Secondary accession number(s): O88726, Q9R1U4, Q9Z0K3

Entry history

Integrated into UniProtKB/Swiss-Prot:	June 20, 2001
Last sequence update:	June 20, 2001
Last modified:	January 19, 2010
This is version 91 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)