Reviewed, UniProtKB/Swiss-Prot P78536 (ADA17_HUMAN)

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
    Snake venom-like protease
    CD_antigen=CD156b

Gene names

Name:	ADAM17
Synonyms:	CSVP, TACE

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	824 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.
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.
Subunit structure	Interacts with MAD2L1 and MUC1. Ref.5
Subcellular location	Membrane; Single-pass type I membrane protein.
Tissue specificity	Ubiquitously expressed. 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.
Induction	In arthritis-affected cartilage.
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 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.
Post-translational modification	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-819 but decreases phosphorylation of Ser-791. Ref.4 Ref.6 Ref.7 Ref.8
Sequence similarities	Contains 1 disintegrin domain. Contains 1 peptidase M12B domain.

Ontologies

Keywords
Biological process	Notch signaling pathway
Cellular component	Membrane
Coding sequence diversity	Alternative splicing Polymorphism
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
Technical term	3D-structure Complete proteome Direct protein sequencing
Gene Ontology (GO)
Biological process	B cell differentiation Inferred from sequence or structural similarity. 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 sequence or structural similarity. Source: UniProtKB cell adhesion mediated by integrin Inferred from direct assay. Source: UniProtKB epidermal growth factor receptor signaling pathway Inferred from direct assay. Source: UniProtKB germinal center formation Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of interleukin-8 production Inferred from mutant phenotype. Source: UniProtKB neutrophil mediated immunity Inferred by curator. Source: UniProtKB positive regulation of T cell chemotaxis Inferred from mutant phenotype. Source: UniProtKB positive regulation of cell growth Inferred from mutant phenotype. Source: UniProtKB positive regulation of cell proliferation Inferred from mutant phenotype. Source: UniProtKB positive regulation of chemokine production Inferred from mutant phenotype. Source: UniProtKB positive regulation of cyclin-dependent protein kinase activity during G1/S Inferred from direct assay. Source: UniProtKB positive regulation of epidermal growth factor receptor activity Inferred from direct assay. Source: UniProtKB positive regulation of protein amino acid phosphorylation Inferred from mutant phenotype. Source: UniProtKB positive regulation of transforming growth factor beta receptor signaling pathway Inferred from sequence or structural similarity. Source: UniProtKB regulation of mast cell apoptosis Inferred from sequence or structural similarity. Source: UniProtKB response to drug Inferred from sequence or structural similarity. Source: UniProtKB response to high density lipoprotein stimulus Inferred from direct assay. Source: UniProtKB response to hypoxia Inferred from direct assay. Source: UniProtKB response to lipopolysaccharide Inferred from direct assay. Source: UniProtKB spleen development Inferred from sequence or structural similarity. Source: UniProtKB wound healing, spreading of epidermal cells Inferred from expression pattern. Source: UniProtKB
Cellular component	actin cytoskeleton Inferred from direct assay. Source: UniProtKB apical plasma membrane Inferred from direct assay. Source: UniProtKB cell surface Ref.2 Inferred from direct assay. Source: UniProtKB cytoplasm Inferred from direct assay. Source: HPA integral to plasma membrane Inferred from direct assay. Source: UniProtKB membrane raft Inferred from direct assay. Source: UniProtKB
Molecular function	PDZ domain binding Inferred from physical interaction. Source: UniProtKB SH3 domain binding Inferred from physical interaction. Source: UniProtKB integrin binding Inferred from physical interaction. Source: UniProtKB interleukin-6 receptor binding Inferred from physical interaction. Source: UniProtKB metalloendopeptidase activity Ref.1 Ref.2 Inferred from direct assay. Source: UniProtKB zinc ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
MAD2L1	Q13257	2	EBI-78188,EBI-78203

Alternative products

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

Isoform A (identifier: P78536-1)

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 B (identifier: P78536-2)

The sequence of this isoform differs from the canonical sequence as follows:
     695-824: Missing.

Note: No experimental confirmation available.

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

PRO_0000029088

Chain

215 – 824

610

Disintegrin and metalloproteinase domain-containing protein 17

PRO_0000029089

Regions

Topological domain

215 – 671

457

Extracellular Potential

Transmembrane

672 – 692

21

Potential

Topological domain

693 – 824

132

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

Motif

741 – 748

8

SH3-binding Potential

Compositional bias

96 – 99

4

Poly-Val

Compositional bias

564 – 602

39

Cys-rich

Sites

Active site

406

1

Metal binding

184

1

Zinc; in inhibited form By similarity

Metal binding

405

1

Zinc; catalytic

Metal binding

409

1

Zinc; catalytic

Metal binding

415

1

Zinc; catalytic

Amino acid modifications

Modified residue

379

1

Phosphotyrosine Ref.7

Modified residue

382

1

Phosphoserine Ref.7

Modified residue

735

1

Phosphothreonine; by MAPK Ref.4

Modified residue

791

1

Phosphoserine Ref.7 Ref.8

Modified residue

819

1

Phosphoserine

Glycosylation

103

1

N-linked (GlcNAc...) Potential

Glycosylation

157

1

N-linked (GlcNAc...) Potential

Glycosylation

174

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

594

1

N-linked (GlcNAc...) Potential

Disulfide bond

225 ↔ 333

Disulfide bond

365 ↔ 469

Disulfide bond

423 ↔ 453

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

695 – 824

130

Missing in isoform B.

VSP_005478

Natural variant

162

1

K → E: dbSNP rs34431503.

VAR_051586

Natural variant

202

1

R → G: dbSNP rs2230818.

VAR_051587

Experimental info

Sequence conflict

109

1

V → A in AAC39721. Ref.3

Sequence conflict

563

1

D → N in AAC39721. Ref.3

Sequence conflict

801

1

T → A in AAC39721. Ref.3

Sequence conflict

818

1

D → N in AAC39721. Ref.3

Secondary structure

1

.

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824

Helix Strand Turn

Details...

Beta strand

224 – 231

8

Helix

233 – 238

6

Helix

244 – 263

20

Beta strand

269 – 271

3

Beta strand

276 – 284

9

Beta strand

309 – 311

3

Helix

314 – 324

11

Helix

326 – 329

4

Beta strand

332 – 339

8

Helix

344 – 346

3

Beta strand

349 – 351

3

Beta strand

362 – 365

4

Beta strand

369 – 371

3

Turn

372 – 375

4

Beta strand

376 – 378

3

Beta strand

382 – 389

8

Helix

396 – 410

15

Beta strand

422 – 424

3

Helix

427 – 429

3

Helix

445 – 448

4

Helix

452 – 469

18

Sequences

	Sequence		Length	Mass (Da)
	Isoform A [UniParc]. Last modified May 1, 1997. Version 1. Checksum: 5B1032F6B88A837F	FASTA	824	93,021
	10 20 30 40 50 60 MRQSLLFLTS VVPFVLAPRP PDDPGFGPHQ RLEKLDSLLS DYDILSLSNI QQHSVRKRDL 70 80 90 100 110 120 QTSTHVETLL TFSALKRHFK LYLTSSTERF SQNFKVVVVD GKNESEYTVK WQDFFTGHVV 130 140 150 160 170 180 GEPDSRVLAH IRDDDVIIRI NTDGAEYNIE PLWRFVNDTK DKRMLVYKSE DIKNVSRLQS 190 200 210 220 230 240 PKVCGYLKVD NEELLPKGLV DREPPEELVH RVKRRADPDP MKNTCKLLVV ADHRFYRYMG 250 260 270 280 290 300 RGEESTTTNY LIELIDRVDD IYRNTSWDNA GFKGYGIQIE QIRILKSPQE VKPGEKHYNM 310 320 330 340 350 360 AKSYPNEEKD AWDVKMLLEQ FSFDIAEEAS KVCLAHLFTY QDFDMGTLGL AYVGSPRANS 370 380 390 400 410 420 HGGVCPKAYY SPVGKKNIYL NSGLTSTKNY GKTILTKEAD LVTTHELGHN FGAEHDPDGL 430 440 450 460 470 480 AECAPNEDQG GKYVMYPIAV SGDHENNKMF SNCSKQSIYK TIESKAQECF QERSNKVCGN 490 500 510 520 530 540 SRVDEGEECD PGIMYLNNDT CCNSDCTLKE GVQCSDRNSP CCKNCQFETA QKKCQEAINA 550 560 570 580 590 600 TCKGVSYCTG NSSECPPPGN AEDDTVCLDL GKCKDGKCIP FCEREQQLES CACNETDNSC 610 620 630 640 650 660 KVCCRDLSGR CVPYVDAEQK NLFLRKGKPC TVGFCDMNGK CEKRVQDVIE RFWDFIDQLS 670 680 690 700 710 720 INTFGKFLAD NIVGSVLVFS LIFWIPFSIL VHCVDKKLDK QYESLSLFHP SNVEMLSSMD 730 740 750 760 770 780 SASVRIIKPF PAPQTPGRLQ PAPVIPSAPA APKLDHQRMD TIQEDPSTDS HMDEDGFEKD 790 800 810 820 PFPNSSTAAK SFEDLTDHPV TRSEKAASFK LQRQNRVDSK ETEC
	Isoform B. Checksum: 9DD63A5B13490AA1	FASTA	694	78,543
	10 20 30 40 50 60 MRQSLLFLTS VVPFVLAPRP PDDPGFGPHQ RLEKLDSLLS DYDILSLSNI QQHSVRKRDL 70 80 90 100 110 120 QTSTHVETLL TFSALKRHFK LYLTSSTERF SQNFKVVVVD GKNESEYTVK WQDFFTGHVV 130 140 150 160 170 180 GEPDSRVLAH IRDDDVIIRI NTDGAEYNIE PLWRFVNDTK DKRMLVYKSE DIKNVSRLQS 190 200 210 220 230 240 PKVCGYLKVD NEELLPKGLV DREPPEELVH RVKRRADPDP MKNTCKLLVV ADHRFYRYMG 250 260 270 280 290 300 RGEESTTTNY LIELIDRVDD IYRNTSWDNA GFKGYGIQIE QIRILKSPQE VKPGEKHYNM 310 320 330 340 350 360 AKSYPNEEKD AWDVKMLLEQ FSFDIAEEAS KVCLAHLFTY QDFDMGTLGL AYVGSPRANS 370 380 390 400 410 420 HGGVCPKAYY SPVGKKNIYL NSGLTSTKNY GKTILTKEAD LVTTHELGHN FGAEHDPDGL 430 440 450 460 470 480 AECAPNEDQG GKYVMYPIAV SGDHENNKMF SNCSKQSIYK TIESKAQECF QERSNKVCGN 490 500 510 520 530 540 SRVDEGEECD PGIMYLNNDT CCNSDCTLKE GVQCSDRNSP CCKNCQFETA QKKCQEAINA 550 560 570 580 590 600 TCKGVSYCTG NSSECPPPGN AEDDTVCLDL GKCKDGKCIP FCEREQQLES CACNETDNSC 610 620 630 640 650 660 KVCCRDLSGR CVPYVDAEQK NLFLRKGKPC TVGFCDMNGK CEKRVQDVIE RFWDFIDQLS 670 680 690 INTFGKFLAD NIVGSVLVFS LIFWIPFSIL VHCV

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha." Moss M.L., Jin S.-L.C., Milla M.E., Burkhart W., Carter H.L., Chen W.-J., Clay W.C., Didsbury J.R., Hassler D., Hoffman C.R., Kost T.A., Lambert M.H., Leesnitzer M.A., McCauley P., McGeehan G., Mitchell J., Moyer M., Pahel G. , Rocque W., Overton L.K., Schoenen F., Seaton T., Su J.-L., Warner J., Willard D., Becherer J.D. Nature 385:733-736(1997) [PubMed: 9034191] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM A), PARTIAL PROTEIN SEQUENCE. Tissue: Leukocyte and Monocyte.
[2]	"A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells." Black R.A., Rauch C.T., Kozlosky C.J., Peschon J.J., Slack J.L., Wolfson M.F., Castner B.J., Stocking K.L., Reddy P., Srinivasan S., Nelson N., Bioani N., Schooley K.A., Gerhart M., Davis R., Fitzner J.N., Johnson R.S., Paxton R.J., March C.J., Cerretti D.P. Nature 385:729-733(1997) [PubMed: 9034190] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS A AND B).
[3]	"TNF-alpha convertase enzyme from human arthritis-affected cartilage: isolation of cDNA by differential display, expression of the active enzyme, and regulation of TNF-alpha." Patel I.R., Attur M.G., Patel R.N., Stuchin S.A., Abagyan R.A., Abramson S.B., Amin A.R. J. Immunol. 160:4570-4579(1998) [PubMed: 9574564] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM A). Tissue: Cartilage.
[4]	"Extracellular signal-regulated kinase phosphorylates tumor necrosis factor alpha-converting enzyme at threonine 735: a potential role in regulated shedding." Diaz-Rodriguez E., Montero J.C., Esparis-Ogando A., Yuste L., Pandiella A. Mol. Biol. Cell 13:2031-2044(2002) [PubMed: 12058067] [Abstract] Cited for: PHOSPHORYLATION AT THR-735.
[5]	"Tumor necrosis factor-alpha converting enzyme/ADAM 17 mediates MUC1 shedding." Thathiah A., Blobel C.P., Carson D.D. J. Biol. Chem. 278:3386-3394(2003) [PubMed: 12441351] [Abstract] Cited for: INTERACTION WITH MUC1, FUNCTION.
[6]	"Characterization of growth factor-induced serine phosphorylation of tumor necrosis factor-alpha converting enzyme and of an alternatively translated polypeptide." Fan H., Turck C.W., Derynck R. J. Biol. Chem. 278:18617-18627(2003) [PubMed: 12621058] [Abstract] Cited for: PHOSPHORYLATION.
[7]	"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks." Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M. Cell 127:635-648(2006) [PubMed: 17081983] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-379; SER-382 AND SER-791, MASS SPECTROMETRY. Tissue: Epithelium.
[8]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-791, MASS SPECTROMETRY.
[9]	"Crystal structure of the catalytic domain of human tumor necrosis factor-alpha-converting enzyme." Maskos K., Fernandez-Catalan C., Huber R., Bourenkov G.P., Bartunik H., Ellestad G.A., Reddy P., Wolfson M.F., Rauch C.T., Castner B.J., Davis R., Clarke H.R.G., Petersen M., Fitzner J.N., Cerretti D.P., March C.J., Paxton R.J., Black R.A., Bode W. Proc. Natl. Acad. Sci. U.S.A. 95:3408-3412(1998) [PubMed: 9520379] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 219-473.
+	Additional computationally mapped references.

Web resources

Wikipedia

Tumor necrosis factor alpha-converting enzyme entry

Cross-references

Sequence databases

EMBLGenBankDDBJ

U86755 mRNA. Translation: AAB51586.1.
U69611 mRNA. Translation: AAB51514.1.
U69612 mRNA. Translation: AAB53014.1.
U92649 mRNA. Translation: AAC39721.1.

IPI

IPI00029606.
IPI00288894.

RefSeq

NP_003174.3.

UniGene

Hs.404914

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1BKC	X-ray	2.00	A/C	219-474	[»]
			E	219-474	[»]
			I	219-474	[»]
1ZXC	X-ray	2.28	A/B	215-477	[»]
2A8H	X-ray	2.30	A/B	215-477	[»]
2DDF	X-ray	1.70	A/B	218-474	[»]
2FV5	X-ray	2.10	A/B	216-475	[»]
2FV9	X-ray	2.02	A/B	218-475	[»]
2I47	X-ray	1.90	A/B/C/D	212-492	[»]
2OI0	X-ray	2.00	A	216-477	[»]
3B92	X-ray	2.00	A	216-474	[»]
3CKI	X-ray	2.30	A	219-474	[»]
3E8R	X-ray	1.90	A/B	215-477	[»]
3EDZ	X-ray	1.90	A/B	215-477	[»]
3EWJ	X-ray	1.80	A/B	215-477	[»]

ModBase

Search...

Protein-protein interaction databases

IntAct

P78536. 1 interaction.

Protein family/group databases

MEROPS

M12.217.

PTM databases

PhosphoSite

P78536.

Proteomic databases

PRIDE

P78536.

Genome annotation databases

Ensembl

ENSG00000151694. Homo sapiens. [Contig view]

GeneID

6868.

KEGG

hsa:6868.

UCSC

uc002qzu.1. human.
uc010ewy.1. human.

Organism-specific databases

GeneCards

GC02M009580.

H-InvDB

HIX0029904.

HGNC

HGNC:195. ADAM17.

HPA

HPA010738.

MIM

603639. gene.

PharmGKB

PA24512.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

P78536.

HOVERGEN

P78536.

OMA

P78536. LKPGVQC.

Enzyme and pathway databases

BRENDA

3.4.24.86. 247.

Pathway_Interaction_DB

p75ntrpathway. p75(NTR)-mediated signaling.
tnfpathway. TNF receptor signaling pathway.

Reactome

REACT_11061. Signalling by NGF.
REACT_9417. Signaling by EGFR.

Gene expression databases

Bgee

P78536.

CleanEx

HS_ADAM17.

GermOnline

ENSG00000151694. Homo sapiens.

Family and domain databases

InterPro

IPR001762. Blood-coag_inhib_Disintegrin.
IPR018358. Disintegrin_CS.
IPR001818. Pept_M10A_M12B.
IPR006025. Pept_M_Zn_BS.
IPR001590. Peptidase_M12B.
[Graphical view]

Pfam

PF00200. Disintegrin. 1 hit.
PF01421. Reprolysin. 1 hit.
[Graphical view]

ProDom

PD000664. Disintegrin. 1 hit.
[Graphical view] [Entries sharing at least one domain]

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

NextBio

26807.

SOURCE

Search...

Entry information

Entry name

ADA17_HUMAN

Accession

Primary (citable) accession number: P78536
Secondary accession number(s): O60226

Entry history

Integrated into UniProtKB/Swiss-Prot:	June 20, 2001
Last sequence update:	May 1, 1997
Last modified:	July 7, 2009
This is version 109 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)