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O75173 (ATS4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 148. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
A disintegrin and metalloproteinase with thrombospondin motifs 4

Short name=ADAM-TS 4
Short name=ADAM-TS4
Short name=ADAMTS-4
EC=3.4.24.82
Alternative name(s):
ADMP-1
Aggrecanase-1
Gene names
Name:ADAMTS4
Synonyms:KIAA0688
ORF Names:UNQ769/PRO1563
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length837 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Cleaves aggrecan, a cartilage proteoglycan, and may be involved in its turnover. May play an important role in the destruction of aggrecan in arthritic diseases. Could also be a critical factor in the exacerbation of neurodegeneration in Alzheimer disease. Cleaves aggrecan at the '392-Glu-|-Ala-393' site.

Catalytic activity

Glutamyl endopeptidase; bonds cleaved include 370-Thr-Glu-Gly-Glu-|-Ala-Arg-Gly-Ser-377 in the interglobular domain of mammalian aggrecan.

Cofactor

Binds 1 zinc ion per subunit. Ref.9

Subunit structure

Interacts with SRPX2. Ref.8

Subcellular location

Secretedextracellular spaceextracellular matrix By similarity.

Tissue specificity

Expressed in brain, lung and heart. Expressed at very low level in placenta and skeletal muscles.

Induction

By IL1/interleukin-1.

Domain

The spacer domain and the TSP type-1 domains are important for a tight interaction with the extracellular matrix.

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.

Glycosylated. Can be O-fucosylated by POFUT2 on a serine or a threonine residue found within the consensus sequence C1-X(2)-(S/T)-C2-G of the TSP type-1 repeat domains where C1 and C2 are the first and second cysteine residue of the repeat, respectively. Fucosylated repeats can then be further glycosylated by the addition of a beta-1,3-glucose residue by the glucosyltransferase, B3GALTL. Fucosylation mediates the efficient secretion of ADAMTS family members. Also can be C-glycosylated with one or two mannose molecules on tryptophan residues within the consensus sequence W-X-X-W of the TPRs, and N-glycosylated. These other glycosylations can also facilitate secretion By similarity.

Sequence similarities

Contains 1 disintegrin domain.

Contains 1 peptidase M12B domain.

Contains 1 TSP type-1 domain.

Caution

Has sometimes been referred to as ADAMTS2.

Sequence caution

The sequence BAA31663.2 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 5151 Potential
Propeptide52 – 212161
PRO_0000029164
Chain213 – 837625A disintegrin and metalloproteinase with thrombospondin motifs 4
PRO_0000029165

Regions

Domain218 – 428211Peptidase M12B
Domain437 – 51983Disintegrin
Domain520 – 57556TSP type-1
Region686 – 837152Spacer
Motif192 – 1998Cysteine switch By similarity
Compositional bias247 – 2526Poly-Ala
Compositional bias577 – 685109Cys-rich

Sites

Active site3621 Ref.9
Metal binding1941Zinc; in inhibited form By similarity
Metal binding3611Zinc; catalytic
Metal binding3651Zinc; catalytic
Metal binding3711Zinc; catalytic

Amino acid modifications

Glycosylation681N-linked (GlcNAc...) Potential
Disulfide bond293 ↔ 345 Ref.9
Disulfide bond322 ↔ 327 Ref.9
Disulfide bond339 ↔ 423 Ref.9
Disulfide bond377 ↔ 407 Ref.9
Disulfide bond449 ↔ 472 Ref.9
Disulfide bond460 ↔ 482 Ref.9
Disulfide bond467 ↔ 501 Ref.9
Disulfide bond495 ↔ 506 Ref.9
Disulfide bond532 ↔ 569 By similarity
Disulfide bond536 ↔ 574 By similarity
Disulfide bond547 ↔ 559 By similarity

Natural variations

Natural variant41T → I. Ref.6
Corresponds to variant rs17855814 [ dbSNP | Ensembl ].
VAR_030636
Natural variant771A → T. Ref.3
Corresponds to variant rs34448954 [ dbSNP | Ensembl ].
VAR_057073
Natural variant3041D → N. Ref.6
Corresponds to variant rs17855813 [ dbSNP | Ensembl ].
VAR_030637
Natural variant3691M → V. Ref.6
Corresponds to variant rs17855812 [ dbSNP | Ensembl ].
VAR_030638
Natural variant5521P → T. Ref.6
Corresponds to variant rs17855815 [ dbSNP | Ensembl ].
VAR_030639
Natural variant5641T → A. Ref.6
Corresponds to variant rs17855816 [ dbSNP | Ensembl ].
VAR_030640
Natural variant6261Q → R. Ref.1 Ref.3 Ref.4
Corresponds to variant rs4233367 [ dbSNP | Ensembl ].
VAR_022450
Natural variant8361R → K.
Corresponds to variant rs11807350 [ dbSNP | Ensembl ].
VAR_030641

Experimental info

Sequence conflict3061D → G in AAQ89245. Ref.4
Sequence conflict6821G → R in AAL02262. Ref.2

Secondary structure

....................................................... 837
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
O75173 [UniParc].

Last modified January 11, 2011. Version 3.
Checksum: 0C05299D7FB23A8D

FASTA83790,197
        10         20         30         40         50         60 
MSQTGSHPGR GLAGRWLWGA QPCLLLPIVP LSWLVWLLLL LLASLLPSAR LASPLPREEE 

        70         80         90        100        110        120 
IVFPEKLNGS VLPGSGAPAR LLCRLQAFGE TLLLELEQDS GVQVEGLTVQ YLGQAPELLG 

       130        140        150        160        170        180 
GAEPGTYLTG TINGDPESVA SLHWDGGALL GVLQYRGAEL HLQPLEGGTP NSAGGPGAHI 

       190        200        210        220        230        240 
LRRKSPASGQ GPMCNVKAPL GSPSPRPRRA KRFASLSRFV ETLVVADDKM AAFHGAGLKR 

       250        260        270        280        290        300 
YLLTVMAAAA KAFKHPSIRN PVSLVVTRLV ILGSGEEGPQ VGPSAAQTLR SFCAWQRGLN 

       310        320        330        340        350        360 
TPEDSDPDHF DTAILFTRQD LCGVSTCDTL GMADVGTVCD PARSCAIVED DGLQSAFTAA 

       370        380        390        400        410        420 
HELGHVFNML HDNSKPCISL NGPLSTSRHV MAPVMAHVDP EEPWSPCSAR FITDFLDNGY 

       430        440        450        460        470        480 
GHCLLDKPEA PLHLPVTFPG KDYDADRQCQ LTFGPDSRHC PQLPPPCAAL WCSGHLNGHA 

       490        500        510        520        530        540 
MCQTKHSPWA DGTPCGPAQA CMGGRCLHMD QLQDFNIPQA GGWGPWGPWG DCSRTCGGGV 

       550        560        570        580        590        600 
QFSSRDCTRP VPRNGGKYCE GRRTRFRSCN TEDCPTGSAL TFREEQCAAY NHRTDLFKSF 

       610        620        630        640        650        660 
PGPMDWVPRY TGVAPQDQCK LTCQAQALGY YYVLEPRVVD GTPCSPDSSS VCVQGRCIHA 

       670        680        690        700        710        720 
GCDRIIGSKK KFDKCMVCGG DGSGCSKQSG SFRKFRYGYN NVVTIPAGAT HILVRQQGNP 

       730        740        750        760        770        780 
GHRSIYLALK LPDGSYALNG EYTLMPSPTD VVLPGAVSLR YSGATAASET LSGHGPLAQP 

       790        800        810        820        830 
LTLQVLVAGN PQDTRLRYSF FVPRPTPSTP RPTPQDWLHR RAQILEILRR RPWAGRK 

« Hide

References

« Hide 'large scale' references
[1]"Purification and cloning of aggrecanase-1: a member of the ADAMTS family of proteins."
Tortorella M.D., Burn T.C., Pratta M.A., Abbaszade I., Hollis J.M., Liu R.-Q., Rosenfeld S.A., Copeland R.A., Decicco C.P., Wynn R., Rockwell A., Yang F., Duke J.L., Solomon K., George H., Bruckner R., Nagase H., Itoh Y. expand/collapse author list , Ellis D.M., Ross H., Wiswall B.H., Murphy K., Hillman M.C. Jr., Hollis G.F., Newton R.C., Magolda R.L., Trzaskos J.M., Arner E.C.
Science 284:1664-1666(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT ARG-626.
[2]"ADAMTS-4 genomic locus."
Sawaji Y., Nagase H., Saklatvala J., Clark A.R.
Submitted (JUL-2001) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]"Prediction of the coding sequences of unidentified human genes. X. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro."
Ishikawa K., Nagase T., Suyama M., Miyajima N., Tanaka A., Kotani H., Nomura N., Ohara O.
DNA Res. 5:169-176(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANTS THR-77 AND ARG-626.
Tissue: Brain.
[4]"The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment."
Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J., Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P., Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E. expand/collapse author list , Heldens S., Huang A., Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D., Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L., Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C., Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J., Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.
Genome Res. 13:2265-2270(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT ARG-626.
[5]"The DNA sequence and biological annotation of human chromosome 1."
Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. expand/collapse author list , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.
Nature 441:315-321(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANTS ILE-4; ASN-304; VAL-369; THR-552 AND ALA-564.
Tissue: Brain.
[7]"The thrombospondin motif of aggrecanase-1 (ADAMTS-4) is critical for aggrecan substrate recognition and cleavage."
Tortorella M.D., Pratta M.A., Liu R.-Q., Abbaszade I., Ross H., Burn T.C., Arner E.C.
J. Biol. Chem. 275:25791-25797(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: PARTIAL PROTEIN SEQUENCE, CHARACTERIZATION.
[8]"Epileptic and developmental disorders of the speech cortex: ligand/receptor interaction of wild-type and mutant SRPX2 with the plasminogen activator receptor uPAR."
Royer-Zemmour B., Ponsole-Lenfant M., Gara H., Roll P., Leveque C., Massacrier A., Ferracci G., Cillario J., Robaglia-Schlupp A., Vincentelli R., Cau P., Szepetowski P.
Hum. Mol. Genet. 17:3617-3630(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH SRPX2.
[9]"Crystal structures of the two major aggrecan degrading enzymes, ADAMTS4 and ADAMTS5."
Mosyak L., Georgiadis K., Shane T., Svenson K., Hebert T., McDonagh T., Mackie S., Olland S., Lin L., Zhong X., Kriz R., Reifenberg E.L., Collins-Racie L.A., Corcoran C., Freeman B., Zollner R., Marvell T., Vera M. expand/collapse author list , Sum P.E., Lavallie E.R., Stahl M., Somers W.
Protein Sci. 17:16-21(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 213-520 ALONE AND IN COMPLEX WITH INHIBITOR, ACTIVE SITE, COFACTOR, ZINC-BINDING SITES, DISULFIDE BONDS.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AF148213 mRNA. Translation: AAD41494.1.
AY044847 Genomic DNA. Translation: AAL02262.1.
AB014588 mRNA. Translation: BAA31663.2. Different initiation.
AY358886 mRNA. Translation: AAQ89245.1.
AL590714 Genomic DNA. Translation: CAH72146.1.
BC063293 mRNA. Translation: AAH63293.1.
PIRT00355.
RefSeqNP_005090.3. NM_005099.4.
UniGeneHs.211604.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2RJPX-ray2.80A/B/C/D213-520[»]
3B2ZX-ray2.80A/B/C/D/E/F/G/H213-520[»]
ProteinModelPortalO75173.
SMRO75173. Positions 215-805.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid114885. 4 interactions.
IntActO75173. 2 interactions.
STRING9606.ENSP00000356975.

Chemistry

BindingDBO75173.
ChEMBLCHEMBL2318.

Protein family/group databases

MEROPSM12.221.

PTM databases

PhosphoSiteO75173.

Proteomic databases

PaxDbO75173.
PRIDEO75173.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000367996; ENSP00000356975; ENSG00000158859.
GeneID9507.
KEGGhsa:9507.
UCSCuc001fyt.4. human.

Organism-specific databases

CTD9507.
GeneCardsGC01M161159.
H-InvDBHIX0001237.
HGNCHGNC:220. ADAMTS4.
HPACAB025876.
MIM603876. gene.
neXtProtNX_O75173.
PharmGKBPA24548.
HUGESearch...
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG271890.
HOGENOMHOG000004799.
HOVERGENHBG004313.
InParanoidO75173.
KOK07764.
OMAHAGCDRI.
OrthoDBEOG7WDN1M.
PhylomeDBO75173.
TreeFamTF331949.

Enzyme and pathway databases

BioCycMetaCyc:ENSG00000158859-MONOMER.
BRENDA3.4.24.82. 2681.
ReactomeREACT_118779. Extracellular matrix organization.

Gene expression databases

ArrayExpressO75173.
BgeeO75173.
CleanExHS_ADAMTS4.
GenevestigatorO75173.

Family and domain databases

Gene3D3.40.390.10. 1 hit.
InterProIPR010294. ADAM_spacer1.
IPR024079. MetalloPept_cat_dom.
IPR001590. Peptidase_M12B.
IPR013273. Peptidase_M12B_ADAM-TS.
IPR002870. Peptidase_M12B_N.
IPR000884. Thrombospondin_1_rpt.
[Graphical view]
PfamPF05986. ADAM_spacer1. 1 hit.
PF01562. Pep_M12B_propep. 1 hit.
PF01421. Reprolysin. 1 hit.
PF00090. TSP_1. 1 hit.
[Graphical view]
PRINTSPR01857. ADAMTSFAMILY.
SMARTSM00209. TSP1. 1 hit.
[Graphical view]
SUPFAMSSF82895. SSF82895. 1 hit.
PROSITEPS50215. ADAM_MEPRO. 1 hit.
PS50092. TSP1. 1 hit.
PS00142. ZINC_PROTEASE. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSADAMTS4. human.
EvolutionaryTraceO75173.
GeneWikiADAMTS4.
GenomeRNAi9507.
NextBio35624.
PMAP-CutDBO75173.
PROO75173.
SOURCESearch...

Entry information

Entry nameATS4_HUMAN
AccessionPrimary (citable) accession number: O75173
Secondary accession number(s): Q5VTW2 expand/collapse secondary AC list , Q6P4Q8, Q6UWA8, Q9UN83
Entry history
Integrated into UniProtKB/Swiss-Prot: December 1, 2000
Last sequence update: January 11, 2011
Last modified: April 16, 2014
This is version 148 of the entry and version 3 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 1

Human chromosome 1: entries, gene names and cross-references to MIM