Reviewed, UniProtKB/Swiss-Prot O14672 (ADA10_HUMAN)

Names and origin

Protein names

Recommended name:
    ADAM 10
    EC=3.4.24.81
Alternative name(s):
    A disintegrin and metalloproteinase domain 10
    Mammalian disintegrin-metalloprotease
    Kuzbanian protein homolog
    CDw156
    CD_antigen=CD156c

Gene names

Name:	ADAM10
Synonyms:	KUZ, MADM

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

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

Protein attributes

Sequence length	748 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 at '76-Ala-|-Val-77' to its mature soluble form. 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 By similarity.
Catalytic activity	Endopeptidase of broad specificity.
Cofactor	Binds 1 zinc ion By similarity.
Subunit structure	Interacts with ephrin-A2 By similarity.
Subcellular location	Cell membrane; Single-pass type I membrane protein. Intracytoplasmic membrane; 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.
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.
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 process	Notch signaling pathway
Cellular component	Cell membrane Membrane
Domain	SH3-binding Signal Transmembrane
Ligand	Metal-binding Zinc
Molecular function	Hydrolase Metalloprotease Protease
PTM	Cleavage on pair of basic residues Glycoprotein Zymogen
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	Notch signaling pathway Inferred from sequence or structural similarity. Source: UniProtKB cell-cell signaling Non-traceable author statement. Source: UniProtKB constitutive protein ectodomain proteolysis Inferred from direct assay. Source: UniProtKB in utero embryonic development Inferred from sequence or structural similarity. Source: UniProtKB integrin-mediated signaling pathway Ref.2 Non-traceable author statement. Source: UniProtKB negative regulation of cell adhesion Ref.2 Inferred from direct assay. Source: UniProtKB protein amino acid phosphorylation Inferred from sequence or structural similarity. Source: UniProtKB
Cellular component	Golgi-associated vesicle Ref.4 Inferred from direct assay. Source: UniProtKB cell surface Ref.4 Inferred from direct assay. Source: UniProtKB integral to membrane Ref.2 Non-traceable author statement. Source: UniProtKB nucleus Inferred from sequence or structural similarity. Source: UniProtKB
Molecular function	integrin binding Ref.2 Non-traceable author statement. Source: UniProtKB metalloendopeptidase activity Ref.2 Non-traceable author statement. Source: UniProtKB protein homodimerization activity Inferred from sequence or structural similarity. Source: UniProtKB protein kinase binding Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
AR	P10275	1	EBI-1536151,EBI-608057

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view
Molecule processing
	Signal peptide	1 – 19	19	Potential
	Propeptide	20 – 213	194	By similarity
	Chain	214 – 748	535	ADAM 10
Regions
	Topological domain	20 – 672	653	Extracellular Potential
	Transmembrane	673 – 693	21	Potential
	Topological domain	694 – 748	55	Cytoplasmic Potential
	Domain	220 – 456	237	Peptidase M12B
	Domain	457 – 551	95	Disintegrin
	Motif	171 – 178	8	Cysteine switch By similarity
	Motif	708 – 715	8	SH3-binding Potential
	Motif	722 – 728	7	SH3-binding Potential
	Compositional bias	555 – 673	119	Cys-rich
Sites
	Active site	384	1
	Metal binding	173	1	Zinc (in inhibited form) By similarity
	Metal binding	383	1	Zinc (catalytic)
	Metal binding	387	1	Zinc (catalytic)
	Metal binding	393	1	Zinc (catalytic)
Amino acid modifications
	Glycosylation	267	1	N-linked (GlcNAc...) Potential
	Glycosylation	278	1	N-linked (GlcNAc...)
	Glycosylation	439	1	N-linked (GlcNAc...) Potential
	Glycosylation	551	1	N-linked (GlcNAc...) Potential
	Disulfide bond	222 ↔ 313		By similarity
	Disulfide bond	344 ↔ 451		By similarity
	Disulfide bond	399 ↔ 435		By similarity
	Disulfide bond	503 ↔ 511		By similarity
	Disulfide bond	524 ↔ 543		By similarity
	Disulfide bond	530 ↔ 562		By similarity
	Disulfide bond	555 ↔ 567		By similarity
	Disulfide bond	572 ↔ 598		By similarity
	Disulfide bond	580 ↔ 607		By similarity
	Disulfide bond	582 ↔ 597		By similarity
Experimental info
	Sequence conflict	162	1	N → SERLKLRLRKLMSLELWTSC CLPCALLLHSWKKAVNSHCL YFKDFWGFSEIY in CAA88463. Ref.2
	Sequence conflict	212	1	K → R in CAA88463. Ref.2
	Sequence conflict	296	1	G → S in CAA88463. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	O14672-1 [UniParc]. Last modified January 1, 1998. Version 1. Checksum: 0881E65B17022A71	FASTA	748	84,142
	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

References

	« Hide 'large scale' referencesShow '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: 9305925] [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: 8694785] [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: 9016778] [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: 12475894] [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: 11477090] [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: 11511685] [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: 11786905] [Abstract] Cited for: FUNCTION.
[8]	"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: 16263699] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-278, MASS SPECTROMETRY. Tissue: Platelet.

Cross-references

Sequence databases

EMBLGenBankDDBJ

AF009615 mRNA. Translation: AAC51766.1.
Z48579 mRNA. Translation: CAA88463.1.

RefSeq

NP_001101.1.

UniGene

Hs.578508

3D structure databases

PDBMSD

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1M1I	model	-	A	207-453	[»]

SMR

O14672. Positions 496-646.

ModBase

Search...

Protein-protein interaction databases

IntAct

O14672.

Protein family/group databases

MEROPS

M12.210.

Genome annotation databases

Ensembl

ENSG00000137845. Homo sapiens. [Contig view]

GeneID

102.

KEGG

hsa:102.

Organism-specific databases

H-InvDB

HIX0012283.

HGNC

HGNC:188. ADAM10.

HPA

CAB001709.

MIM

602192. gene.

PharmGKB

PA24505.

GenAtlas

Search...

GeneCards

Search...

GeneLynx

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Phylogenomic databases

HOGENOM

O14672.

HOVERGEN

O14672.

Enzyme and pathway databases

Reactome

REACT_299. Signaling by Notch.
REACT_9417. Signaling by EGFR.

Gene expression databases

ArrayExpress

O14672.

CleanEx

HS_ADAM10.

GermOnline

ENSG00000137845. Homo sapiens.

Family and domain databases

InterPro

IPR001762. Blood-coag_inhib_Disintegrin.
IPR001818. Pept_M10A_M12B.
IPR006025. Pept_M_Zn_BS.
IPR001590. Peptidase_M12B.
IPR002870. Peptidase_M12B_N.
[Graphical view]

Gene3D

G3DSA:4.10.70.10. Blood-coag_inhib_Disintegrin. 1 hit.

Pfam

PF00200. Disintegrin. 1 hit.
PF01562. Pep_M12B_propep. 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]

BLOCKS

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Other Resources

SOURCE

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ProtoNet

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Entry information

Entry name

ADA10_HUMAN

Accession

Primary (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:	July 22, 2008
This is version 83 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)