Reviewed, UniProtKB/Swiss-Prot O75173 (ATS4_HUMAN)

Names and origin

Protein names

Recommended name:
    A disintegrin and metalloproteinase with thrombospondin motifs 4
      Short name=ADAMTS-4
      Short name=ADAM-TS 4
      Short name=ADAM-TS4
    EC=3.4.24.82
Alternative name(s):
    Aggrecanase-1
    ADMP-1

Gene names

Name:	ADAMTS4
Synonyms:	KIAA0688
ORF Names:	UNQ769/PRO1563

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	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.
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 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.
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.

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 Direct protein sequencing
Gene Ontology (GO)
Biological process	proteolysis Traceable author statement. Source: ProtInc skeletal system development Ref.1 Traceable author statement. Source: ProtInc
Cellular component	extracellular space Inferred from direct assay. Source: UniProtKB proteinaceous extracellular matrix Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	metalloendopeptidase activity Inferred from electronic annotation. Source: InterPro protease binding Inferred from physical interaction. Source: UniProtKB zinc ion binding Inferred from electronic annotation. Source: UniProtKB-KW
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: dbSNP rs17855814. Ref.6

VAR_030636

Natural variant

77

1

A → T: dbSNP rs34448954.

VAR_057073

Natural variant

304

1

D → N: dbSNP rs17855813. Ref.6

VAR_030637

Natural variant

369

1

M → V: dbSNP rs17855812. Ref.6

VAR_030638

Natural variant

552

1

P → T: dbSNP rs17855815. Ref.6

VAR_030639

Natural variant

564

1

T → A: dbSNP rs17855816. Ref.6

VAR_030640

Natural variant

626

1

R → Q: dbSNP rs4233367. Ref.6 Ref.2 Ref.5

VAR_022450

Natural variant

836

1

R → K: dbSNP rs11807350.

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 – 253

16

Helix

256 – 258

3

Beta strand

262 – 271

10

Beta strand

274 – 276

3

Helix

285 – 295

11

Helix

296 – 298

3

Beta strand

311 – 317

7

Turn

322 – 324

3

Beta strand

328 – 333

6

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 – 423

6

Helix

439 – 442

4

Helix

445 – 453

9

Beta strand

463 – 465

3

Turn

466 – 468

3

Beta strand

471 – 474

4

Beta strand

481 – 484

4

Beta strand

494 – 496

3

Beta strand

499 – 506

8

Sequences

	Sequence		Length	Mass (Da)
	O75173-1 [UniParc]. Last modified December 1, 2000. Version 2. Checksum: 5DF9C9AC137DF41F	FASTA	837	90,225
	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 LTCQARALGY 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: 10356395] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[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], VARIANT GLN-626.
[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: 9734811] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT THR-77. 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: 12975309] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[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: 16710414] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], VARIANT GLN-626.
[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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANTS ILE-4; ASN-304; VAL-369; THR-552; ALA-564 AND GLN-626. 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: 10827174] [Abstract] Cited for: PARTIAL PROTEIN SEQUENCE, CHARACTERIZATION.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBLGenBankDDBJ

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.

UniGene

Hs.211604

3D structure databases

PDBPDBe

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	[»]

ModBase

Search...

Protein family/group databases

MEROPS

M12.221.

Proteomic databases

PRIDE

O75173.

Genome annotation databases

Ensembl

ENSG00000158859. Homo sapiens. [Contig view]

GeneID

9507.

KEGG

hsa:9507.

Organism-specific databases

GeneCards

GC01M159426.

H-InvDB

HIX0001237.

HGNC

HGNC:220. ADAMTS4.

MIM

603876. gene.

PharmGKB

PA24548.

HUGE

Search...

GenAtlas

Search...

Phylogenomic databases

HOGENOM

O75173.

HOVERGEN

O75173.

Enzyme and pathway databases

BRENDA

3.4.24.82. 247.

Gene expression databases

ArrayExpress

O75173.

Bgee

O75173.

CleanEx

HS_ADAMTS4.

GermOnline

ENSG00000158859. Homo sapiens.

Family and domain databases

InterPro

IPR010294. ADAM_spacer1.
IPR018358. Disintegrin_CS.
IPR006025. Pept_M_Zn_BS.
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]

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 Resources

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:	December 1, 2000
Last modified:	June 16, 2009
This is version 103 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)