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Reviewed, UniProtKB/Swiss-Prot P78536 (ADA17_HUMAN)

Last modified June 10, 2008. Version 95. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (8) | Third-party data | Customize display text xml rdf/xml gff fasta
Names and origin · General annotation (Comments) · Ontologies · Binary interactions · Alternative products · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents

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Names and origin

Protein namesADAM 17 [Precursor]
Also known as:
     EC 3.4.24.86
     A disintegrin and metalloproteinase domain 17
     TNF-alpha-converting enzyme
     TNF-alpha convertase
     Snake venom-like protease
     CD156b antigen
Gene names
Name: ADAM17
Synonyms: CSVP, TACE
OrganismHomo sapiens (Human)
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo
Protein existenceEvidence at protein level.

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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.

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.

Sequence similarities

Contains 1 disintegrin domain.

Contains 1 peptidase M12B domain.

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Ontologies

Keywords

   Biological processNotch signaling pathway
   Cellular componentMembrane
   Coding sequence diversityAlternative splicing
   DomainSH3-binding
Signal
Transmembrane
   LigandMetal-binding
Zinc
   Molecular functionHydrolase
Metalloprotease
Protease
   PTMCleavage on pair of basic residues
Glycoprotein
Phosphoprotein
Zymogen
   Technical term3D-structure
Direct protein sequencing

Gene Ontology (GO)

   Biological processcell-cell signaling Ref.2

Traceable author statement. Source: ProtInc

   Cellular componentintegral to plasma membrane Ref.3

Traceable author statement. Source: ProtInc

   Molecular functionmetallopeptidase activity Ref.1

Traceable author statement. Source: ProtInc

protein binding

Inferred from physical interaction. Source: IntAct

Complete GO annotation...

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Binary interactions

With

Entry

#Exp.

IntAct

Notes

MAD2L1Q132572EBI-78188,EBI-78203

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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.
Notes: No experimental confirmation available.

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Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical view

Molecule processing

Signal peptide1 – 1717 Potential
Propeptide18 – 214197
Chain215 – 824610ADAM 17

Regions

Topological domain215 – 671457Extracellular Potential
Transmembrane672 – 69221 Potential
Topological domain693 – 824132Cytoplasmic Potential
Domain223 – 474252Peptidase M12B
Domain475 – 56389Disintegrin
Region603 – 67169Crambin-like
Motif182 – 1898Cysteine switch By similarity
Motif731 – 7388SH3-binding Potential
Motif741 – 7488SH3-binding Potential
Compositional bias96 – 994Poly-Val
Compositional bias564 – 60239Cys-rich

Sites

Active site4061
Metal binding1841Zinc (in inhibited form) By similarity
Metal binding4051Zinc (catalytic)
Metal binding4091Zinc (catalytic)
Metal binding4151Zinc (catalytic)

Amino acid modifications

Modified residue3791Phosphotyrosine
Modified residue3821Phosphoserine
Modified residue7351Phosphothreonine; by MAPK
Modified residue7911Phosphoserine
Modified residue8191Phosphoserine
Glycosylation1031N-linked (GlcNAc...) Potential
Glycosylation1571N-linked (GlcNAc...) Potential
Glycosylation1741N-linked (GlcNAc...) Potential
Glycosylation2641N-linked (GlcNAc...) Potential
Glycosylation4521N-linked (GlcNAc...) Potential
Glycosylation4981N-linked (GlcNAc...) Potential
Glycosylation5391N-linked (GlcNAc...) Potential
Glycosylation5511N-linked (GlcNAc...) Potential
Glycosylation5941N-linked (GlcNAc...) Potential
Disulfide bond225 ↔ 333
Disulfide bond365 ↔ 469
Disulfide bond423 ↔ 453
Disulfide bond534 ↔ 555 By similarity
Disulfide bond573 ↔ 582 By similarity
Disulfide bond578 ↔ 591 By similarity
Disulfide bond593 ↔ 600 By similarity

Natural variations

Alternative sequence695 – 824130Missing in isoform B.

Experimental info

Sequence conflict1091V → A in AAC39721. Ref.3
Sequence conflict5631D → N in AAC39721. Ref.3
Sequence conflict8011T → A in AAC39721. Ref.3
Sequence conflict8181D → N in AAC39721. Ref.3

Secondary structure

1 ......................................... 824
Helix Strand Turn

Details...

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Sequences

Sequence LengthMass (Da)Tools
Isoform A [UniParc].

Last modified May 1, 1997. Version 1.
Checksum: 5B1032F6B88A837F

FASTA82493,021
        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

« Hide

Isoform B [UniParc].

Checksum: 9DD63A5B13490AA1
Show »

69478,543

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References

« Hide '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. expand/collapse author list , 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]"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.

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Web resources

Wikipedia

Tumor necrosis factor alpha-converting enzyme entry

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Cross-references

Sequence databases

U86755 mRNA. Translation: AAB51586.1.