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O14672 (ADA10_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 143. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (8) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Disintegrin and metalloproteinase domain-containing protein 10

Short name=ADAM 10
EC=3.4.24.81
Alternative name(s):
CDw156
Kuzbanian protein homolog
Mammalian disintegrin-metalloprotease
CD_antigen=CD156c
Gene names
Name:ADAM10
Synonyms:KUZ, MADM
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length748 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Cleaves the membrane-bound precursor of TNF-alpha at '76-Ala-|-Val-77' to its mature soluble form. Responsible for the proteolytical release of soluble JAM3 from endothelial cells surface. Responsible for the proteolytic release of several other cell-surface proteins, including heparin-binding epidermal growth-like factor, ephrin-A2 and for constitutive and regulated alpha-secretase cleavage of amyloid precursor protein (APP). Contributes to the normal cleavage of the cellular prion protein. Involved in the cleavage of the adhesion molecule L1 at the cell surface and in released membrane vesicles, suggesting a vesicle-based protease activity. Controls also the proteolytic processing of Notch and mediates lateral inhibition during neurogenesis. Responsible for the FasL ectodomain shedding and for the generation of the remnant ADAM10-processed FasL (FasL APL) transmembrane form. Also cleaves the ectodomain of the integral membrane proteins CORIN and ITM2B. May regulate the EFNA5-EPHA3 signaling. Ref.4 Ref.5 Ref.7 Ref.8 Ref.10 Ref.11 Ref.14 Ref.16

Catalytic activity

Endopeptidase of broad specificity.

Cofactor

Binds 1 zinc ion By similarity.

Subunit structure

Interacts with EPHA2 By similarity. Forms a ternary EFNA5-EPHA3-ADAM10 complex mediating EFNA5 extracellular domain shedding by ADAM10 which regulates the EFNA5-EPHA3 complex internalization and function, the cleavage occurs in trans, with ADAM10 and its substrate being on the membranes of opposing cells. Ref.8

Subcellular location

Cell membrane; Single-pass type I membrane protein. Endomembrane system; Single-pass type I membrane protein. Note: Is localized in the plasma membrane but is predominantly expressed in the Golgi apparatus and in released membrane vesicles derived likely from the Golgi.

Tissue specificity

Expressed in spleen, lymph node, thymus, peripheral blood leukocyte, bone marrow, cartilage, chondrocytes and fetal liver. Ref.3 Ref.6

Induction

In osteoarthritis affected-cartilage.

Domain

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.

The Cys-rich region C-terminal to the disintegrin domain functions as a substrate-recognition module, it recognizes the EFNA5-EPHA3 Complex but not the individual proteins By similarity.

Post-translational modification

The precursor is cleaved by a furin endopeptidase By similarity.

Sequence similarities

Contains 1 disintegrin domain.

Contains 1 peptidase M12B domain.

Ontologies

Keywords
   Biological processNotch signaling pathway
   Cellular componentCell membrane
Membrane
   Coding sequence diversityPolymorphism
   DomainSH3-binding
Signal
Transmembrane
Transmembrane helix
   LigandMetal-binding
Zinc
   Molecular functionHydrolase
Metalloprotease
Protease
   PTMCleavage on pair of basic residues
Disulfide bond
Glycoprotein
Zymogen
   Technical term3D-structure
Complete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processNotch receptor processing

Traceable author statement. Source: Reactome

Notch signaling pathway

Inferred from sequence or structural similarity. Source: UniProtKB

PMA-inducible membrane protein ectodomain proteolysis

Inferred from mutant phenotype PubMed 18676862. Source: BHF-UCL

cell-cell signaling

Non-traceable author statement PubMed 12714508. Source: UniProtKB

collagen catabolic process

Traceable author statement. Source: Reactome

constitutive protein ectodomain proteolysis

Inferred from direct assay PubMed 12714508. Source: UniProtKB

epidermal growth factor receptor signaling pathway

Traceable author statement. Source: Reactome

extracellular matrix disassembly

Traceable author statement. Source: Reactome

extracellular matrix organization

Traceable author statement. Source: Reactome

in utero embryonic development

Inferred from sequence or structural similarity. Source: UniProtKB

integrin-mediated signaling pathway

Non-traceable author statement Ref.2. Source: UniProtKB

membrane protein ectodomain proteolysis

Inferred from direct assay PubMed 12714508Ref.10Ref.11. Source: UniProtKB

monocyte activation

Inferred from mutant phenotype PubMed 11831872. Source: BHF-UCL

negative regulation of cell adhesion

Inferred from direct assay PubMed 12714508. Source: UniProtKB

positive regulation of T cell chemotaxis

Inferred from mutant phenotype PubMed 18373975. Source: BHF-UCL

positive regulation of cell growth

Inferred from mutant phenotype PubMed 18373975. Source: BHF-UCL

positive regulation of cell migration

Inferred from mutant phenotype PubMed 18373975. Source: BHF-UCL

positive regulation of cell proliferation

Inferred from mutant phenotype PubMed 18373975. Source: BHF-UCL

protein phosphorylation

Inferred from sequence or structural similarity. Source: UniProtKB

response to tumor necrosis factor

Inferred from direct assay PubMed 11831872. Source: BHF-UCL

   Cellular_componentGolgi apparatus

Inferred from direct assay Ref.4. Source: UniProtKB

Golgi-associated vesicle

Inferred from direct assay Ref.4. Source: UniProtKB

cell surface

Inferred from direct assay Ref.4. Source: UniProtKB

cytoplasm

Inferred from sequence or structural similarity. Source: UniProtKB

extracellular vesicular exosome

Inferred from direct assay PubMed 20458337. Source: UniProt

integral component of membrane

Non-traceable author statement Ref.2. Source: UniProtKB

nucleus

Inferred from sequence or structural similarity. Source: UniProtKB

plasma membrane

Traceable author statement. Source: Reactome

postsynaptic density

Inferred from electronic annotation. Source: Ensembl

   Molecular_functionendopeptidase activity

Inferred from sequence or structural similarity. Source: UniProtKB

integrin binding

Non-traceable author statement Ref.2. Source: UniProtKB

metalloendopeptidase activity

Inferred from mutant phenotype Ref.11. Source: UniProtKB

metallopeptidase activity

Inferred from direct assay Ref.4. Source: UniProtKB

protein homodimerization activity

Inferred from sequence or structural similarity. Source: UniProtKB

protein kinase binding

Inferred from sequence or structural similarity. Source: UniProtKB

receptor binding

Non-traceable author statement PubMed 12176995. Source: UniProtKB

zinc ion binding

Inferred from electronic annotation. Source: InterPro

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 1919 Potential
Propeptide20 – 213194 By similarity
PRO_0000029066
Chain214 – 748535Disintegrin and metalloproteinase domain-containing protein 10
PRO_0000029067

Regions

Topological domain20 – 672653Extracellular Potential
Transmembrane673 – 69321Helical; Potential
Topological domain694 – 74855Cytoplasmic Potential
Domain220 – 456237Peptidase M12B
Domain457 – 55195Disintegrin
Motif171 – 1788Cysteine switch By similarity
Motif708 – 7158SH3-binding Potential
Motif722 – 7287SH3-binding Potential
Compositional bias555 – 673119Cys-rich

Sites

Active site3841
Metal binding1731Zinc; in inhibited form By similarity
Metal binding3831Zinc; catalytic
Metal binding3871Zinc; catalytic
Metal binding3931Zinc; catalytic

Amino acid modifications

Glycosylation2671N-linked (GlcNAc...) Potential
Glycosylation2781N-linked (GlcNAc...) Ref.9 Ref.12 Ref.13
Glycosylation4391N-linked (GlcNAc...) Potential
Glycosylation5511N-linked (GlcNAc...) Potential
Disulfide bond222 ↔ 313 By similarity
Disulfide bond344 ↔ 451 By similarity
Disulfide bond399 ↔ 435 By similarity
Disulfide bond484 ↔ 515 By similarity
Disulfide bond503 ↔ 511 By similarity
Disulfide bond524 ↔ 543 By similarity
Disulfide bond530 ↔ 562 By similarity
Disulfide bond555 ↔ 567 By similarity
Disulfide bond572 ↔ 598 By similarity
Disulfide bond580 ↔ 607 By similarity
Disulfide bond582 ↔ 597 By similarity
Disulfide bond594 ↔ 639 By similarity
Disulfide bond632 ↔ 645 By similarity

Natural variations

Natural variant1761H → Y in a cutaneous metastatic melanoma sample; somatic mutation. Ref.17
VAR_066309

Experimental info

Sequence conflict1621N → SERLKLRLRKLMSLELWTSC CLPCALLLHSWKKAVNSHCL YFKDFWGFSEIY in CAA88463. Ref.2
Sequence conflict2121K → R in CAA88463. Ref.2
Sequence conflict2961G → S in CAA88463. Ref.2

Sequences

Sequence LengthMass (Da)Tools
O14672 [UniParc].

Last modified January 1, 1998. Version 1.
Checksum: 0881E65B17022A71

FASTA74884,142
        10         20         30         40         50         60 
MVLLRVLILL LSWAAGMGGQ YGNPLNKYIR HYEGLSYNVD SLHQKHQRAK RAVSHEDQFL 

        70         80         90        100        110        120 
RLDFHAHGRH FNLRMKRDTS LFSDEFKVET SNKVLDYDTS HIYTGHIYGE EGSFSHGSVI 

       130        140        150        160        170        180 
DGRFEGFIQT RGGTFYVEPA ERYIKDRTLP FHSVIYHEDD INYPHKYGPQ GGCADHSVFE 

       190        200        210        220        230        240 
RMRKYQMTGV EEVTQIPQEE HAANGPELLR KKRTTSAEKN TCQLYIQTDH LFFKYYGTRE 

       250        260        270        280        290        300 
AVIAQISSHV KAIDTIYQTT DFSGIRNISF MVKRIRINTT ADEKDPTNPF RFPNIGVEKF 

       310        320        330        340        350        360 
LELNSEQNHD DYCLAYVFTD RDFDDGVLGL AWVGAPSGSS GGICEKSKLY SDGKKKSLNT 

       370        380        390        400        410        420 
GIITVQNYGS HVPPKVSHIT FAHEVGHNFG SPHDSGTECT PGESKNLGQK ENGNYIMYAR 

       430        440        450        460        470        480 
ATSGDKLNNN KFSLCSIRNI SQVLEKKRNN CFVESGQPIC GNGMVEQGEE CDCGYSDQCK 

       490        500        510        520        530        540 
DECCFDANQP EGRKCKLKPG KQCSPSQGPC CTAQCAFKSK SEKCRDDSDC AREGICNGFT 

       550        560        570        580        590        600 
ALCPASDPKP NFTDCNRHTQ VCINGQCAGS ICEKYGLEEC TCASSDGKDD KELCHVCCMK 

       610        620        630        640        650        660 
KMDPSTCAST GSVQWSRHFS GRTITLQPGS PCNDFRGYCD VFMRCRLVDA DGPLARLKKA 

       670        680        690        700        710        720 
IFSPELYENI AEWIVAHWWA VLLMGIALIM LMAGFIKICS VHTPSSNPKL PPPKPLPGTL 

       730        740 
KRRRPPQPIQ QPQRQRPRES YQMGHMRR 

« Hide

References

« Hide 'large scale' references
[1]"Identification and characterization of a pro-tumor necrosis factor-alpha-processing enzyme from the ADAM family of zinc metalloproteases."
Rosendahl M.S., Ko S.C., Long D.L., Brewer M.T., Rosenzweig B., Hedl E., Anderson L., Pyle S.M., Moreland J., Meyers M.A., Kohno T., Lyons D., Lichenstein H.S.
J. Biol. Chem. 272:24588-24593(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 216-237.
[2]"Molecular cloning of MADM: a catalytically active mammalian disintegrin-metalloprotease expressed in various cell types."
Howard L., Mitchell S., Lu X., Griffiths S., Glynn P.
Biochem. J. 317:45-50(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 109-748.
[3]"Expression of members of a novel membrane linked metalloproteinase family (ADAM) in human articular chondrocytes."
McKie N., Edwards T., Dallas D.J., Houghton A., Stringer B., Graham R., Russell G., Croucher P.I.
Biochem. Biophys. Res. Commun. 230:335-339(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: TISSUE SPECIFICITY.
[4]"ADAM10-mediated cleavage of L1 adhesion molecule at the cell surface and in released membrane vesicles."
Gutwein P., Mechtersheimer S., Riedle S., Stoeck A., Gast D., Joumaa S., Zentgraf H., Fogel M., Altevogt P.
FASEB J. 17:292-294(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[5]"The disintegrins ADAM10 and TACE contribute to the constitutive and phorbol ester-regulated normal cleavage of the cellular prion protein."
Vincent B., Paitel E., Saftig P., Frobert Y., Hartmann D., De Strooper B., Grassi J., Lopez-Perez E., Checler F.
J. Biol. Chem. 276:37743-37746(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[6]"ADAM-10 protein is present in human articular cartilage primarily in the membrane-bound form and is upregulated in osteoarthritis and in response to IL-1alpha in bovine nasal cartilage."
Chubinskaya S., Mikhail R., Deutsch A., Tindal M.H.
J. Histochem. Cytochem. 49:1165-1176(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: TISSUE SPECIFICITY.
[7]"Platelet-activating factor receptor and ADAM10 mediate responses to Staphylococcus aureus in epithelial cells."
Lemjabbar H., Basbaum C.
Nat. Med. 8:41-46(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[8]"Adam meets Eph: an ADAM substrate recognition module acts as a molecular switch for ephrin cleavage in trans."
Janes P.W., Saha N., Barton W.A., Kolev M.V., Wimmer-Kleikamp S.H., Nievergall E., Blobel C.P., Himanen J.P., Lackmann M., Nikolov D.B.
Cell 123:291-304(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION IN A COMPLEX WITH EFNA5 AND EPHA3, FUNCTION IN EFNA5-EPHA3 SIGNALING.
[9]"Elucidation of N-glycosylation sites on human platelet proteins: a glycoproteomic approach."
Lewandrowski U., Moebius J., Walter U., Sickmann A.
Mol. Cell. Proteomics 5:226-233(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-278.
Tissue: Platelet.
[10]"The Fas ligand intracellular domain is released by ADAM10 and SPPL2a cleavage in T-cells."
Kirkin V., Cahuzac N., Guardiola-Serrano F., Huault S., Luckerath K., Friedmann E., Novac N., Wels W.S., Martoglio B., Hueber A.O., Zornig M.
Cell Death Differ. 14:1678-1687(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN CLEAVAGE OF FASLG.
[11]"Substrate requirements for SPPL2b-dependent regulated intramembrane proteolysis."
Martin L., Fluhrer R., Haass C.
J. Biol. Chem. 284:5662-5670(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN CLEAVAGE OF ITM2B.
[12]"Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry."
Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.
J. Proteome Res. 8:651-661(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-278.
Tissue: Liver.
[13]"Mass-spectrometric identification and relative quantification of N-linked cell surface glycoproteins."
Wollscheid B., Bausch-Fluck D., Henderson C., O'Brien R., Bibel M., Schiess R., Aebersold R., Watts J.D.
Nat. Biotechnol. 27:378-386(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-278.
Tissue: Leukemic T-cell.
[14]"Junctional adhesion molecule-C is a soluble mediator of angiogenesis."
Rabquer B.J., Amin M.A., Teegala N., Shaheen M.K., Tsou P.S., Ruth J.H., Lesch C.A., Imhof B.A., Koch A.E.
J. Immunol. 185:1777-1785(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN CLEAVAGE OF JAM3.
[15]"Initial characterization of the human central proteome."
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.
BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[16]"Ectodomain shedding and autocleavage of the cardiac membrane protease corin."
Jiang J., Wu S., Wang W., Chen S., Peng J., Zhang X., Wu Q.
J. Biol. Chem. 286:10066-10072(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN CLEAVAGE OF CORIN.
[17]"Analysis of the disintegrin-metalloproteinases family reveals ADAM29 and ADAM7 are often mutated in melanoma."
Wei X., Moncada-Pazos A., Cal S., Soria-Valles C., Gartner J., Rudloff U., Lin J.C., Rosenberg S.A., Lopez-Otin C., Samuels Y.
Hum. Mutat. 32:E2148-E2175(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT TYR-176.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AF009615 mRNA. Translation: AAC51766.1.
Z48579 mRNA. Translation: CAA88463.1.
RefSeqNP_001101.1. NM_001110.3.
UniGeneHs.172028.
Hs.578508.
Hs.745136.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1M1Imodel-A207-453[»]
ProteinModelPortalO14672.
SMRO14672. Positions 215-650.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid106616. 10 interactions.
DIPDIP-39889N.
IntActO14672. 5 interactions.
MINTMINT-5000775.
STRING9606.ENSP00000260408.

Chemistry

BindingDBO14672.
ChEMBLCHEMBL5028.

Protein family/group databases

MEROPSM12.210.

PTM databases

PhosphoSiteO14672.

Proteomic databases

PaxDbO14672.
PRIDEO14672.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000260408; ENSP00000260408; ENSG00000137845.
GeneID102.
KEGGhsa:102.
UCSCuc002afd.1. human.

Organism-specific databases

CTD102.
GeneCardsGC15M058887.
HGNCHGNC:188. ADAM10.
HPACAB001709.
MIM602192. gene.
neXtProtNX_O14672.
Orphanet178307. Reticulate acropigmentation of Kitamura.
PharmGKBPA24505.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG271989.
HOGENOMHOG000008148.
HOVERGENHBG050455.
InParanoidO14672.
KOK06704.
OMAHEDDIKY.
OrthoDBEOG7SBNNQ.
PhylomeDBO14672.
TreeFamTF352021.

Enzyme and pathway databases

BioCycMetaCyc:ENSG00000137845-MONOMER.
BRENDA3.4.24.81. 2681.
ReactomeREACT_111102. Signal Transduction.
REACT_116125. Disease.
REACT_118779. Extracellular matrix organization.
REACT_2001. Receptor-ligand binding initiates the second proteolytic cleavage of Notch receptor.
SignaLinkO14672.

Gene expression databases

ArrayExpressO14672.
BgeeO14672.
CleanExHS_ADAM10.
GenevestigatorO14672.

Family and domain databases

Gene3D3.40.390.10. 1 hit.
4.10.70.10. 1 hit.
InterProIPR027053. ADAM_10.
IPR001762. Blood-coag_inhib_Disintegrin.
IPR024079. MetalloPept_cat_dom.
IPR001590. Peptidase_M12B.
IPR002870. Peptidase_M12B_N.
[Graphical view]
PANTHERPTHR11905:SF4. PTHR11905:SF4. 1 hit.
PfamPF00200. Disintegrin. 1 hit.
PF01562. Pep_M12B_propep. 1 hit.
[Graphical view]
SMARTSM00050. DISIN. 1 hit.
[Graphical view]
SUPFAMSSF57552. SSF57552. 1 hit.
PROSITEPS50215. ADAM_MEPRO. 1 hit.
PS50214. DISINTEGRIN_2. 1 hit.
PS00142. ZINC_PROTEASE. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSADAM10. human.
GeneWikiADAM10.
GenomeRNAi102.
NextBio385.
PMAP-CutDBO14672.
PROO14672.
SOURCESearch...

Entry information

Entry nameADA10_HUMAN
AccessionPrimary (citable) accession number: O14672
Secondary accession number(s): Q10742, Q92650
Entry history
Integrated into UniProtKB/Swiss-Prot: February 28, 2003
Last sequence update: January 1, 1998
Last modified: April 16, 2014
This is version 143 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

Peptidase families

Classification of peptidase families and list of entries

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 15

Human chromosome 15: entries, gene names and cross-references to MIM

Human cell differentiation molecules

CD nomenclature of surface proteins of human leucocytes and list of entries