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Protein

A disintegrin and metalloproteinase with thrombospondin motifs 4

Gene

ADAMTS4

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

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.

Caution

Has sometimes been referred to as ADAMTS2.Curated

Catalytic activityi

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

Cofactori

Zn2+1 PublicationNote: Binds 1 zinc ion per subunit.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Metal bindingi194Zinc; in inhibited formBy similarity1
Metal bindingi361Zinc; catalytic1 Publication1
Active sitei362PROSITE-ProRule annotation1 Publication1
Metal bindingi365Zinc; catalytic1 Publication1
Metal bindingi371Zinc; catalytic1 Publication1

GO - Molecular functioni

  • metal ion binding Source: UniProtKB-KW
  • metalloendopeptidase activity Source: Reactome
  • metallopeptidase activity Source: ProtInc
  • peptidase activity Source: ProtInc
  • protease binding Source: BHF-UCL

GO - Biological processi

Keywordsi

Molecular functionHydrolase, Metalloprotease, Protease
LigandMetal-binding, Zinc

Enzyme and pathway databases

BioCyciMetaCyc:ENSG00000158859-MONOMER
ReactomeiR-HSA-1474228 Degradation of the extracellular matrix
R-HSA-5083635 Defective B3GALTL causes Peters-plus syndrome (PpS)
R-HSA-5173214 O-glycosylation of TSR domain-containing proteins

Protein family/group databases

MEROPSiM12.221
TCDBi8.A.77.1.7 the sheddase (sheddase) family

Names & Taxonomyi

Protein namesi
Recommended name:
A disintegrin and metalloproteinase with thrombospondin motifs 4 (EC:3.4.24.82)
Short name:
ADAM-TS 4
Short name:
ADAM-TS4
Short name:
ADAMTS-4
Alternative name(s):
ADMP-1
Aggrecanase-1
Gene namesi
Name:ADAMTS4
Synonyms:KIAA0688
ORF Names:UNQ769/PRO1563
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 1

Organism-specific databases

EuPathDBiHostDB:ENSG00000158859.9
HGNCiHGNC:220 ADAMTS4
MIMi603876 gene
neXtProtiNX_O75173

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Extracellular matrix, Secreted

Pathology & Biotechi

Organism-specific databases

DisGeNETi9507
OpenTargetsiENSG00000158859
PharmGKBiPA24548

Chemistry databases

ChEMBLiCHEMBL2318
DrugBankiDB06822 Tinzaparin
GuidetoPHARMACOLOGYi1677

Polymorphism and mutation databases

BioMutaiADAMTS4

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 51Sequence analysisAdd BLAST51
PropeptideiPRO_000002916452 – 212Add BLAST161
ChainiPRO_0000029165213 – 837A disintegrin and metalloproteinase with thrombospondin motifs 4Add BLAST625

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi68N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi293 ↔ 3451 Publication
Disulfide bondi322 ↔ 3271 Publication
Disulfide bondi339 ↔ 4231 Publication
Disulfide bondi377 ↔ 4071 Publication
Disulfide bondi449 ↔ 4721 Publication
Disulfide bondi460 ↔ 4821 Publication
Disulfide bondi467 ↔ 5011 Publication
Disulfide bondi495 ↔ 5061 Publication
Disulfide bondi532 ↔ 569By similarity
Disulfide bondi536 ↔ 574By similarity
Disulfide bondi547 ↔ 559By similarity

Post-translational modificationi

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-X2-(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).By similarity

Keywords - PTMi

Cleavage on pair of basic residues, Disulfide bond, Glycoprotein, Zymogen

Proteomic databases

EPDiO75173
PaxDbiO75173
PeptideAtlasiO75173
PRIDEiO75173
ProteomicsDBi49841

PTM databases

iPTMnetiO75173
PhosphoSitePlusiO75173

Miscellaneous databases

PMAP-CutDBiO75173

Expressioni

Tissue specificityi

Expressed in brain, lung and heart (PubMed:23897278). Expressed at very low level in placenta and skeletal muscles (PubMed:23897278). Isoform 2: Detected in osteoarthritic synovium (PubMed:16723216, PubMed:23897278).2 Publications

Inductioni

By IL1/interleukin-1.

Gene expression databases

BgeeiENSG00000158859 Expressed in 86 organ(s), highest expression level in left coronary artery
CleanExiHS_ADAMTS4
ExpressionAtlasiO75173 baseline and differential
GenevisibleiO75173 HS

Organism-specific databases

HPAiCAB025876
HPA051296
HPA068374

Interactioni

Subunit structurei

Interacts with SRPX2.2 Publications

GO - Molecular functioni

Protein-protein interaction databases

BioGridi114885, 29 interactors
IntActiO75173, 2 interactors
STRINGi9606.ENSP00000356975

Chemistry databases

BindingDBiO75173

Structurei

Secondary structure

1837
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliO75173
SMRiO75173
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiO75173

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini218 – 428Peptidase M12BPROSITE-ProRule annotationAdd BLAST211
Domaini437 – 519DisintegrinAdd BLAST83
Domaini520 – 575TSP type-1PROSITE-ProRule annotationAdd BLAST56

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni686 – 837SpacerAdd BLAST152

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi192 – 199Cysteine switchBy similarity8

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi247 – 252Poly-Ala6
Compositional biasi577 – 685Cys-richAdd BLAST109

Domaini

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.

Keywords - Domaini

Signal

Phylogenomic databases

eggNOGiKOG3538 Eukaryota
ENOG410XPKZ LUCA
GeneTreeiENSGT00900000140774
HOGENOMiHOG000004799
HOVERGENiHBG004313
InParanoidiO75173
KOiK07764
OMAiKFRYGYN
OrthoDBiEOG091G00AX
PhylomeDBiO75173
TreeFamiTF331949

Family and domain databases

Gene3Di2.20.100.10, 1 hit
3.40.390.10, 1 hit
InterProiView protein in InterPro
IPR006586 ADAM_Cys-rich
IPR010294 ADAM_spacer1
IPR024079 MetalloPept_cat_dom_sf
IPR001590 Peptidase_M12B
IPR002870 Peptidase_M12B_N
IPR000884 TSP1_rpt
IPR036383 TSP1_rpt_sf
PfamiView protein in Pfam
PF05986 ADAM_spacer1, 1 hit
PF01562 Pep_M12B_propep, 1 hit
PF01421 Reprolysin, 1 hit
PF00090 TSP_1, 1 hit
SMARTiView protein in SMART
SM00608 ACR, 1 hit
SM00209 TSP1, 1 hit
SUPFAMiSSF82895 SSF82895, 1 hit
PROSITEiView protein in PROSITE
PS50215 ADAM_MEPRO, 1 hit
PS50092 TSP1, 1 hit
PS00142 ZINC_PROTEASE, 1 hit

Sequences (2+)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

This entry has 2 described isoforms and 1 potential isoform that is computationally mapped.iShow all

Isoform 1 (identifier: O75173-1) [UniParc]FASTAAdd to basket

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.

« Hide
        10         20         30         40         50
MSQTGSHPGR GLAGRWLWGA QPCLLLPIVP LSWLVWLLLL LLASLLPSAR
60 70 80 90 100
LASPLPREEE IVFPEKLNGS VLPGSGAPAR LLCRLQAFGE TLLLELEQDS
110 120 130 140 150
GVQVEGLTVQ YLGQAPELLG GAEPGTYLTG TINGDPESVA SLHWDGGALL
160 170 180 190 200
GVLQYRGAEL HLQPLEGGTP NSAGGPGAHI LRRKSPASGQ GPMCNVKAPL
210 220 230 240 250
GSPSPRPRRA KRFASLSRFV ETLVVADDKM AAFHGAGLKR YLLTVMAAAA
260 270 280 290 300
KAFKHPSIRN PVSLVVTRLV ILGSGEEGPQ VGPSAAQTLR SFCAWQRGLN
310 320 330 340 350
TPEDSDPDHF DTAILFTRQD LCGVSTCDTL GMADVGTVCD PARSCAIVED
360 370 380 390 400
DGLQSAFTAA HELGHVFNML HDNSKPCISL NGPLSTSRHV MAPVMAHVDP
410 420 430 440 450
EEPWSPCSAR FITDFLDNGY GHCLLDKPEA PLHLPVTFPG KDYDADRQCQ
460 470 480 490 500
LTFGPDSRHC PQLPPPCAAL WCSGHLNGHA MCQTKHSPWA DGTPCGPAQA
510 520 530 540 550
CMGGRCLHMD QLQDFNIPQA GGWGPWGPWG DCSRTCGGGV QFSSRDCTRP
560 570 580 590 600
VPRNGGKYCE GRRTRFRSCN TEDCPTGSAL TFREEQCAAY NHRTDLFKSF
610 620 630 640 650
PGPMDWVPRY TGVAPQDQCK LTCQAQALGY YYVLEPRVVD GTPCSPDSSS
660 670 680 690 700
VCVQGRCIHA GCDRIIGSKK KFDKCMVCGG DGSGCSKQSG SFRKFRYGYN
710 720 730 740 750
NVVTIPAGAT HILVRQQGNP GHRSIYLALK LPDGSYALNG EYTLMPSPTD
760 770 780 790 800
VVLPGAVSLR YSGATAASET LSGHGPLAQP LTLQVLVAGN PQDTRLRYSF
810 820 830
FVPRPTPSTP RPTPQDWLHR RAQILEILRR RPWAGRK
Length:837
Mass (Da):90,197
Last modified:January 11, 2011 - v3
Checksum:i0C05299D7FB23A8D
GO
Isoform 2 (identifier: O75173-2) [UniParc]FASTAAdd to basket
Also known as: ADAMTS4_v1

The sequence of this isoform differs from the canonical sequence as follows:
     697-837: YGYNNVVTIP...LRRRPWAGRK → CGTAWGSQLA...PALVSCPGRQ

Note: Functional aggrecanase.1 Publication
Show »
Length:846
Mass (Da):90,065
Checksum:iEE5ABC89BD0556D5
GO

Computationally mapped potential isoform sequencesi

There is 1 potential isoform mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
Q5VTW1Q5VTW1_HUMAN
A disintegrin and metalloproteinase...
ADAMTS4
339Annotation score:

Sequence cautioni

The sequence ABC88384 differs from that shown. Reason: Frameshift at position 697.Curated
The sequence BAA31663 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti306D → G in AAQ89245 (PubMed:12975309).Curated1
Sequence conflicti682G → R in AAL02262 (Ref. 3) Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_0306364T → I1 PublicationCorresponds to variant dbSNP:rs17855814Ensembl.1
Natural variantiVAR_05707377A → T1 PublicationCorresponds to variant dbSNP:rs34448954Ensembl.1
Natural variantiVAR_030637304D → N1 PublicationCorresponds to variant dbSNP:rs17855813Ensembl.1
Natural variantiVAR_030638369M → V1 PublicationCorresponds to variant dbSNP:rs17855812Ensembl.1
Natural variantiVAR_030639552P → T1 PublicationCorresponds to variant dbSNP:rs17855815Ensembl.1
Natural variantiVAR_030640564T → A1 PublicationCorresponds to variant dbSNP:rs17855816Ensembl.1
Natural variantiVAR_022450626Q → R3 PublicationsCorresponds to variant dbSNP:rs4233367Ensembl.1
Natural variantiVAR_030641836R → K. Corresponds to variant dbSNP:rs11807350Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_057293697 – 837YGYNN…WAGRK → CGTAWGSQLALQRGHCSLRD TVRPWATGPAFDTASPSGWQ PPGHTPPIQLLRAPADPFNA TPHSPGLAAPKSTDSGDPSA APLGGQEITSLSRLPFLGTG ASDLAGRKRELLLLPHAKTQ WGGAVGVRPAPPLCPNAQAG PALVSCPGRQ in isoform 2. 1 PublicationAdd BLAST141

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF148213 mRNA Translation: AAD41494.1
DQ364570 mRNA Translation: ABC88384.1 Frameshift.
AY044847 Genomic DNA Translation: AAL02262.1
AB014588 mRNA Translation: BAA31663.2 Different initiation.
AY358886 mRNA Translation: AAQ89245.1
AL590714 Genomic DNA No translation available.
BC063293 mRNA Translation: AAH63293.1
CCDSiCCDS1223.1 [O75173-1]
PIRiT00355
RefSeqiNP_001307265.1, NM_001320336.1 [O75173-2]
NP_005090.3, NM_005099.5 [O75173-1]
UniGeneiHs.211604

Genome annotation databases

EnsembliENST00000367996; ENSP00000356975; ENSG00000158859 [O75173-1]
GeneIDi9507
KEGGihsa:9507
UCSCiuc001fyt.5 human [O75173-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF148213 mRNA Translation: AAD41494.1
DQ364570 mRNA Translation: ABC88384.1 Frameshift.
AY044847 Genomic DNA Translation: AAL02262.1
AB014588 mRNA Translation: BAA31663.2 Different initiation.
AY358886 mRNA Translation: AAQ89245.1
AL590714 Genomic DNA No translation available.
BC063293 mRNA Translation: AAH63293.1
CCDSiCCDS1223.1 [O75173-1]
PIRiT00355
RefSeqiNP_001307265.1, NM_001320336.1 [O75173-2]
NP_005090.3, NM_005099.5 [O75173-1]
UniGeneiHs.211604

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2RJPX-ray2.80A/B/C/D213-520[»]
3B2ZX-ray2.80A/B/C/D/E/F/G/H213-520[»]
4WK7X-ray1.24A213-439[»]
4WKEX-ray1.62A213-439[»]
4WKIX-ray1.60A213-439[»]
ProteinModelPortaliO75173
SMRiO75173
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi114885, 29 interactors
IntActiO75173, 2 interactors
STRINGi9606.ENSP00000356975

Chemistry databases

BindingDBiO75173
ChEMBLiCHEMBL2318
DrugBankiDB06822 Tinzaparin
GuidetoPHARMACOLOGYi1677

Protein family/group databases

MEROPSiM12.221
TCDBi8.A.77.1.7 the sheddase (sheddase) family

PTM databases

iPTMnetiO75173
PhosphoSitePlusiO75173

Polymorphism and mutation databases

BioMutaiADAMTS4

Proteomic databases

EPDiO75173
PaxDbiO75173
PeptideAtlasiO75173
PRIDEiO75173
ProteomicsDBi49841

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000367996; ENSP00000356975; ENSG00000158859 [O75173-1]
GeneIDi9507
KEGGihsa:9507
UCSCiuc001fyt.5 human [O75173-1]

Organism-specific databases

CTDi9507
DisGeNETi9507
EuPathDBiHostDB:ENSG00000158859.9
GeneCardsiADAMTS4
H-InvDBiHIX0001237
HGNCiHGNC:220 ADAMTS4
HPAiCAB025876
HPA051296
HPA068374
MIMi603876 gene
neXtProtiNX_O75173
OpenTargetsiENSG00000158859
PharmGKBiPA24548
HUGEiSearch...
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG3538 Eukaryota
ENOG410XPKZ LUCA
GeneTreeiENSGT00900000140774
HOGENOMiHOG000004799
HOVERGENiHBG004313
InParanoidiO75173
KOiK07764
OMAiKFRYGYN
OrthoDBiEOG091G00AX
PhylomeDBiO75173
TreeFamiTF331949

Enzyme and pathway databases

BioCyciMetaCyc:ENSG00000158859-MONOMER
ReactomeiR-HSA-1474228 Degradation of the extracellular matrix
R-HSA-5083635 Defective B3GALTL causes Peters-plus syndrome (PpS)
R-HSA-5173214 O-glycosylation of TSR domain-containing proteins

Miscellaneous databases

ChiTaRSiADAMTS4 human
EvolutionaryTraceiO75173
GeneWikiiADAMTS4
GenomeRNAii9507
PMAP-CutDBiO75173
PROiPR:O75173
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000158859 Expressed in 86 organ(s), highest expression level in left coronary artery
CleanExiHS_ADAMTS4
ExpressionAtlasiO75173 baseline and differential
GenevisibleiO75173 HS

Family and domain databases

Gene3Di2.20.100.10, 1 hit
3.40.390.10, 1 hit
InterProiView protein in InterPro
IPR006586 ADAM_Cys-rich
IPR010294 ADAM_spacer1
IPR024079 MetalloPept_cat_dom_sf
IPR001590 Peptidase_M12B
IPR002870 Peptidase_M12B_N
IPR000884 TSP1_rpt
IPR036383 TSP1_rpt_sf
PfamiView protein in Pfam
PF05986 ADAM_spacer1, 1 hit
PF01562 Pep_M12B_propep, 1 hit
PF01421 Reprolysin, 1 hit
PF00090 TSP_1, 1 hit
SMARTiView protein in SMART
SM00608 ACR, 1 hit
SM00209 TSP1, 1 hit
SUPFAMiSSF82895 SSF82895, 1 hit
PROSITEiView protein in PROSITE
PS50215 ADAM_MEPRO, 1 hit
PS50092 TSP1, 1 hit
PS00142 ZINC_PROTEASE, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiATS4_HUMAN
AccessioniPrimary (citable) accession number: O75173
Secondary accession number(s): Q2HYD0
, Q5VTW2, Q6P4Q8, Q6UWA8, Q9UN83
Entry historyiIntegrated into UniProtKB/Swiss-Prot: December 1, 2000
Last sequence update: January 11, 2011
Last modified: September 12, 2018
This is version 188 of the entry and version 3 of the sequence. See complete history.
Entry statusiReviewed (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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health

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