O75173 (ATS4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	837 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 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 By similarity.
Subunit structure	Interacts with SRPX2. Ref.8
Subcellular location	Secreted › extracellular space › extracellular 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.

Ontologies

Keywords
Cellular component	Extracellular matrix Secreted
Coding sequence diversity	Polymorphism
Domain	Signal
Ligand	Metal-binding Zinc
Molecular function	Hydrolase Metalloprotease Protease
PTM	Cleavage on pair of basic residues Disulfide bond Glycoprotein Zymogen
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	proteolysis Traceable author statement PubMed 10751421. Source: ProtInc skeletal system development Traceable author statement Ref.1. Source: ProtInc
Cellular_component	extracellular space Inferred from direct assay PubMed 14744861. Source: BHF-UCL proteinaceous extracellular matrix Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	metalloendopeptidase activity Inferred from electronic annotation. Source: InterPro metallopeptidase activity Traceable author statement Ref.1. Source: ProtInc zinc ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 51

51

Potential

Propeptide

52 – 212

161

PRO_0000029164

Chain

213 – 837

625

A disintegrin and metalloproteinase with thrombospondin motifs 4

PRO_0000029165

Regions

Domain

218 – 428

211

Peptidase M12B

Domain

437 – 519

83

Disintegrin

Domain

520 – 575

56

TSP type-1

Region

686 – 837

152

Spacer

Motif

192 – 199

8

Cysteine switch By similarity

Compositional bias

247 – 252

6

Poly-Ala

Compositional bias

577 – 685

109

Cys-rich

Sites

Active site

362

1

By similarity

Metal binding

194

1

Zinc; in inhibited form By similarity

Metal binding

361

1

Zinc; catalytic By similarity

Metal binding

365

1

Zinc; catalytic By similarity

Metal binding

371

1

Zinc; catalytic By similarity

Amino acid modifications

Glycosylation

68

1

N-linked (GlcNAc...) Potential

Disulfide bond

339 ↔ 423

By similarity

Disulfide bond

377 ↔ 407

By similarity

Disulfide bond

532 ↔ 569

By similarity

Disulfide bond

536 ↔ 574

By similarity

Disulfide bond

547 ↔ 559

By similarity

Natural variations

Natural variant

4

1

T → I. Ref.6
Corresponds to variant rs17855814 [ dbSNP | Ensembl ].

VAR_030636

Natural variant

77

1

A → T. Ref.3
Corresponds to variant rs34448954 [ dbSNP | Ensembl ].

VAR_057073

Natural variant

304

1

D → N. Ref.6
Corresponds to variant rs17855813 [ dbSNP | Ensembl ].

VAR_030637

Natural variant

369

1

M → V. Ref.6
Corresponds to variant rs17855812 [ dbSNP | Ensembl ].

VAR_030638

Natural variant

552

1

P → T. Ref.6
Corresponds to variant rs17855815 [ dbSNP | Ensembl ].

VAR_030639

Natural variant

564

1

T → A. Ref.6
Corresponds to variant rs17855816 [ dbSNP | Ensembl ].

VAR_030640

Natural variant

626

1

Q → R. Ref.1 Ref.3 Ref.4
Corresponds to variant rs4233367 [ dbSNP | Ensembl ].

VAR_022450

Natural variant

836

1

R → K.
Corresponds to variant rs11807350 [ dbSNP | Ensembl ].

VAR_030641

Experimental info

Sequence conflict

306

1

D → G in AAQ89245. Ref.4

Sequence conflict

682

1

G → R in AAL02262. Ref.2

Secondary structure

1

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837

Helix Strand Turn

Details...

Beta strand

218 – 226

9

Helix

228 – 234

7

Helix

235 – 237

3

Helix

238 – 252

15

Helix

256 – 258

3

Beta strand

262 – 271

10

Beta strand

274 – 276

3

Helix

285 – 296

12

Turn

297 – 299

3

Beta strand

304 – 306

3

Beta strand

311 – 317

7

Turn

322 – 324

3

Beta strand

331 – 333

3

Turn

341 – 343

3

Beta strand

345 – 349

5

Helix

355 – 366

12

Helix

375 – 381

7

Beta strand

393 – 395

3

Helix

406 – 417

12

Turn

418 – 421

4

Helix

422 – 424

3

Helix

439 – 442

4

Helix

445 – 453

9

Beta strand

463 – 465

3

Turn

466 – 468

3

Beta strand

472 – 476

5

Beta strand

479 – 483

5

Beta strand

494 – 496

3

Beta strand

499 – 502

4

Beta strand

505 – 507

3

Sequences

	Sequence		Length	Mass (Da)
	O75173 [UniParc]. Last modified January 11, 2011. Version 3. Checksum: 0C05299D7FB23A8D	FASTA	837	90,197
	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

References

	« Hide 'large scale' referencesShow '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. , 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. , 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. , 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.
+	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.

IPI

IPI00307276.

PIR

T00355.

RefSeq

NP_005090.3. NM_005099.4.

UniGene

Hs.211604.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2RJP	X-ray	2.80	A/B/C/D	213-520	[»]
3B2Z	X-ray	2.80	A/B/C/D/E/F/G/H	213-520	[»]

ProteinModelPortal

O75173.

SMR

O75173. Positions 215-805.

ModBase

Search...

Protein-protein interaction databases

IntAct

O75173. 2 interactions.

STRING

9606.ENSP00000356975.

Protein family/group databases

MEROPS

M12.221.

PTM databases

PhosphoSite

O75173.

Proteomic databases

PaxDb

O75173.

PRIDE

O75173.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000367996; ENSP00000356975; ENSG00000158859.

GeneID

9507.

KEGG

hsa:9507.

UCSC

uc001fyt.4. human.

Organism-specific databases

CTD

9507.

GeneCards

GC01M161159.

H-InvDB

HIX0001237.

HGNC

HGNC:220. ADAMTS4.

HPA

CAB025876.

MIM

603876. gene.

neXtProt

NX_O75173.

PharmGKB

PA24548.

HUGE

Search...

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG271890.

HOGENOM

HOG000004799.

HOVERGEN

HBG004313.

InParanoid

O75173.

KO

K07764.

OMA

HAGCDRI.

OrthoDB

EOG4F4S9C.

PhylomeDB

O75173.

Enzyme and pathway databases

BioCyc

MetaCyc:ENSG00000158859-MONOMER.

BRENDA

3.4.24.82. 2681.

Gene expression databases

ArrayExpress

O75173.

Bgee

O75173.

CleanEx

HS_ADAMTS4.

Genevestigator

O75173.

GermOnline

ENSG00000158859. Homo sapiens.

Family and domain databases

Gene3D

3.40.390.10. 1 hit.

InterPro

IPR010294. ADAM_spacer1.
IPR024079. MetalloPept_cat_dom.
IPR001590. Peptidase_M12B.
IPR013273. Peptidase_M12B_ADAM-TS.
IPR002870. Peptidase_M12B_N.
IPR000884. Thrombospondin_1_rpt.
[Graphical view]

Pfam

PF05986. ADAM_spacer1. 1 hit.
PF01562. Pep_M12B_propep. 1 hit.
PF01421. Reprolysin. 1 hit.
PF00090. TSP_1. 1 hit.
[Graphical view]

PRINTS

PR01857. ADAMTSFAMILY.

SMART

SM00209. TSP1. 1 hit.
[Graphical view]

SUPFAM

SSF82895. TSP1. 1 hit.

PROSITE

PS50215. ADAM_MEPRO. 1 hit.
PS00427. DISINTEGRIN_1. False negative.
PS50214. DISINTEGRIN_2. False negative.
PS50092. TSP1. 1 hit.
PS00142. ZINC_PROTEASE. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

O75173.

ChEMBL

CHEMBL2318.

ChiTaRS

ADAMTS4. human.

EvolutionaryTrace

O75173.

GenomeRNAi

9507.

NextBio

35624.

PMAP-CutDB

O75173.

SOURCE

Search...

Entry information

Entry name

ATS4_HUMAN

Accession

Primary (citable) accession number: O75173
Secondary accession number(s): Q5VTW2 , Q6P4Q8, Q6UWA8, Q9UN83

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 1, 2000
Last sequence update:	January 11, 2011
Last modified:	April 3, 2013
This is version 140 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.