Reviewed, UniProtKB/Swiss-Prot O75173 (ATS4_HUMAN)

Names and origin

Protein names

Recommended name:
    ADAMTS-4
    EC=3.4.24.82
Alternative name(s):
    A disintegrin and metalloproteinase with thrombospondin motifs 4
      Short name(s)=ADAM-TS 4, ADAM-TS4
    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 matrixBy 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 Glycoprotein Zymogen
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	proteolysis Traceable author statement. Source: ProtInc skeletal development Ref.1 Traceable author statement. Source: ProtInc
Cellular component	extracellular space Inferred from direct assay. Source: UniProtKB
Molecular function	metallopeptidase activity Ref.1 Traceable author statement. Source: ProtInc protease binding Inferred from physical interaction. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view
Molecule processing
	Signal peptide	1 – 51	51	Potential
	Propeptide	52 – 212	161
	Chain	213 – 837	625	ADAMTS-4
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.
	Natural variant	304	1	D → N: dbSNP rs17855813.
	Natural variant	369	1	M → V: dbSNP rs17855812.
	Natural variant	552	1	P → T: dbSNP rs17855815.
	Natural variant	564	1	T → A: dbSNP rs17855816.
	Natural variant	626	1	R → Q: dbSNP rs4233367.
	Natural variant	836	1	R → K: dbSNP rs11807350.
Experimental info
	Sequence conflict	77	1	A → T in BAA31663. Ref.3
	Sequence conflict	306	1	D → G in AAQ89245. Ref.4
	Sequence conflict	682	1	G → R in AAL02262. Ref.2

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]. 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.

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.

PIR

T00355.

RefSeq

NP_005090.3.

UniGene

Hs.211604
Hs.705280

3D structure databases

PDBMSD

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.

Genome annotation databases

Ensembl

ENSG00000158859. Homo sapiens. [Contig view]

GeneID

9507.

KEGG

hsa:9507.

Organism-specific databases

H-InvDB

HIX0001237.

HGNC

HGNC:220. ADAMTS4.

MIM

603876. gene.

PharmGKB

PA24548.

HUGE

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GenAtlas

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GeneCards

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GeneLynx

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Phylogenomic databases

HOGENOM

O75173.

HOVERGEN

O75173.

Gene expression databases

ArrayExpress

O75173.

CleanEx

HS_ADAMTS4.

GermOnline

ENSG00000158859. Homo sapiens.

Family and domain databases

InterPro

IPR010294. ADAM_spacer1.
IPR001762. Blood-coag_inhib_Disintegrin.
IPR006025. Pept_M_Zn_BS.
IPR001590. Peptidase_M12B.
IPR013273. Peptidase_M12B_ADAM-TS.
IPR002870. Peptidase_M12B_N.
IPR000884. TSP1.
IPR008085. TSP_1.
[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.
PR01705. TSP1REPEAT.

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]

ProDom

O75173.
[Graphical view] [Entries sharing at least one domain]

BLOCKS

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Other Resources

SOURCE

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ProtoNet

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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:	July 22, 2008
This is version 91 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)