P16035 (TIMP2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Metalloproteinase inhibitor 2

Alternative name(s):
CSC-21K
Tissue inhibitor of metalloproteinases 2
Short name=TIMP-2

Gene names

Name:

TIMP2

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	220 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	Complexes with metalloproteinases (such as collagenases) and irreversibly inactivates them by binding to their catalytic zinc cofactor. Known to act on MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-13, MMP-14, MMP-15, MMP-16 and MMP-19. Ref.6 Ref.8 Ref.12
Subunit structure	Interacts (via the C-terminal) with MMP2 (via the C-terminal PEX domain); the interaction inhibits the MMP2 activity. Ref.11 Ref.12
Subcellular location	Secreted.
Induction	Down-regulated by TGFB1. Ref.1
Post-translational modification	The activity of TIMP2 is dependent on the presence of disulfide bonds.
Sequence similarities	Belongs to the protease inhibitor I35 (TIMP) family. [View classification] Contains 1 NTR domain.

Ontologies

Keywords
Cellular component	Secreted
Domain	Signal
Ligand	Metal-binding Zinc
Molecular function	Metalloenzyme inhibitor Metalloprotease inhibitor Protease inhibitor
PTM	Disulfide bond
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	aging Inferred from electronic annotation. Source: Compara cellular response to organic substance Inferred from electronic annotation. Source: Compara central nervous system development Inferred from electronic annotation. Source: Compara extracellular matrix disassembly Traceable author statement. Source: Reactome negative regulation of Ras protein signal transduction Inferred from electronic annotation. Source: Compara negative regulation of cell proliferation Inferred from electronic annotation. Source: Compara negative regulation of mitotic cell cycle Inferred from electronic annotation. Source: Compara negative regulation of proteolysis Inferred from electronic annotation. Source: Compara positive regulation of MAPK cascade Inferred from electronic annotation. Source: Compara positive regulation of adenylate cyclase activity Inferred from electronic annotation. Source: Compara positive regulation of neuron differentiation Inferred from electronic annotation. Source: Compara regulation of Rap protein signal transduction Inferred from electronic annotation. Source: Compara response to cytokine stimulus Inferred from electronic annotation. Source: Compara response to drug Inferred from electronic annotation. Source: Compara
Cellular_component	basement membrane Inferred from electronic annotation. Source: Compara cell surface Inferred from electronic annotation. Source: Compara extracellular region Traceable author statement. Source: Reactome extracellular space Inferred from electronic annotation. Source: Compara growth cone Inferred from electronic annotation. Source: Compara neuronal cell body Inferred from electronic annotation. Source: Compara
Molecular_function	enzyme activator activity Inferred from electronic annotation. Source: Compara metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW metalloendopeptidase inhibitor activity Traceable author statement Ref.3. Source: ProtInc
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 26

26

Ref.6 Ref.7 Ref.9

Chain

27 – 220

194

Metalloproteinase inhibitor 2

PRO_0000034335

Regions

Domain

27 – 152

126

NTR

Region

27 – 31

5

Involved in metalloproteinase-binding

Region

95 – 96

2

Involved in metalloproteinase-binding

Sites

Metal binding

27

1

Zinc; via amino nitrogen and carbonyl oxygen; shared with metalloproteinase partner By similarity

Amino acid modifications

Disulfide bond

27 ↔ 98

Ref.16

Disulfide bond

29 ↔ 127

Ref.16

Disulfide bond

39 ↔ 152

Ref.16

Disulfide bond

154 ↔ 201

Ref.16

Disulfide bond

159 ↔ 164

Ref.16

Disulfide bond

172 ↔ 193

Ref.16

Experimental info

Sequence conflict

17 – 19

3

LAT → P in AAC50729. Ref.3

Sequence conflict

44 – 50

7

VIRAKAV → GKESGDP Ref.10

Sequence conflict

78

1

M → K AA sequence Ref.6

Sequence conflict

78

1

M → K AA sequence Ref.7

Sequence conflict

82

1

P → I AA sequence Ref.6

Sequence conflict

82

1

P → I AA sequence Ref.7

Sequence conflict

96

1

A → V in CAA38400. Ref.5

Sequence conflict

101

1

S → E AA sequence Ref.6

Sequence conflict

101

1

S → E AA sequence Ref.7

Sequence conflict

118

1

Missing AA sequence Ref.6

Sequence conflict

118

1

Missing AA sequence Ref.7

Sequence conflict

122

1

M → R AA sequence Ref.6

Sequence conflict

122

1

M → R AA sequence Ref.7

Sequence conflict

150

1

M → Q AA sequence Ref.6

Sequence conflict

150

1

M → Q AA sequence Ref.7

Sequence conflict

175

1

M → T AA sequence Ref.6

Sequence conflict

175

1

M → T AA sequence Ref.7

Secondary structure

1

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220

Helix Strand Turn

Details...

Helix

34 – 40

7

Beta strand

41 – 59

19

Beta strand

65 – 81

17

Beta strand

88 – 91

4

Helix

95 – 97

3

Beta strand

104 – 106

3

Beta strand

109 – 118

10

Beta strand

121 – 123

3

Beta strand

130 – 132

3

Helix

133 – 135

3

Helix

138 – 143

6

Turn

144 – 148

5

Helix

149 – 151

3

Beta strand

154 – 158

5

Beta strand

161 – 163

3

Beta strand

171 – 174

4

Helix

176 – 180

5

Beta strand

181 – 185

5

Helix

186 – 190

5

Beta strand

192 – 195

4

Beta strand

201 – 204

4

Sequences

	Sequence		Length	Mass (Da)
	P16035 [UniParc]. Last modified November 1, 1990. Version 2. Checksum: 603E5B1C9F94735D	FASTA	220	24,399
	10 20 30 40 50 60 MGAAARTLRL ALGLLLLATL LRPADACSCS PVHPQQAFCN ADVVIRAKAV SEKEVDSGND 70 80 90 100 110 120 IYGNPIKRIQ YEIKQIKMFK GPEKDIEFIY TAPSSAVCGV SLDVGGKKEY LIAGKAEGDG 130 140 150 160 170 180 KMHITLCDFI VPWDTLSTTQ KKSLNHRYQM GCECKITRCP MIPCYISSPD ECLWMDWVTE 190 200 210 220 KNINGHQAKF FACIKRSDGS CAWYRGAAPP KQEFLDIEDP

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Tissue inhibitor of metalloproteinases-2 (TIMP-2) mRNA expression in tumor cell lines and human tumor tissues." Stetler-Stevenson W.G., Brown P.D., Onisto M., Levy A.T., Liotta L.A. J. Biol. Chem. 265:13933-13938(1990) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], INDUCTION.
[2]	"cDNA cloning and expression of a metalloproteinase inhibitor related to tissue inhibitor of metalloproteinases." Boone T.C., Johnson M.J., de Clerck Y.A., Langley K.E. Proc. Natl. Acad. Sci. U.S.A. 87:2800-2804(1990) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	"Structure and characterization of the human tissue inhibitor of metalloproteinases-2 gene." Hammani K., Blakis A., Morsette D., Bowcock A., Schmutte C., Henriet P., Declerck Y.A. J. Biol. Chem. 271:25498-25505(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. Tissue: Placenta.
[4]	"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]. Tissue: Placenta and Skin.
[5]	Malik K., Sejima H., Aoki T., Iwata K. Submitted (AUG-1990) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE OF 30-214.
[6]	"Tissue inhibitor of metalloproteinase (TIMP-2). A new member of the metalloproteinase inhibitor family." Stetler-Stevenson W.G., Krutzsch H.C., Liotta L.A. J. Biol. Chem. 264:17374-17378(1989) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 27-219, FUNCTION.
[7]	"TIMP-2: identification and characterization of a new member of the metalloproteinase inhibitor family." Stetler-Stevenson W.G., Krutzsch H.C., Liotta L.A. Matrix Suppl. 1:299-306(1992) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 27-219.
[8]	"Human 72-kilodalton type IV collagenase forms a complex with a tissue inhibitor of metalloproteases designated TIMP-2." Goldberg G.I., Marmer B.L., Grant G.A., Eisen A.Z., Wilhelm S., He C. Proc. Natl. Acad. Sci. U.S.A. 86:8207-8211(1989) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 30-51; 124-141 AND 159-173, FUNCTION.
[9]	"Isolation and characterization of tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) from human rheumatoid synovial fluid." Osthues A., Knaueper V., Oberhoff R., Reinke H., Tschesche H. FEBS Lett. 296:16-20(1992) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 27-41. Tissue: Synovial fluid.
[10]	"Characterization of the promoter of the gene encoding human tissue inhibitor of metalloproteinases-2 (TIMP-2)." de Clerck Y.A., Darville M.I., Eeckhout Y., Rousseau G.G. Gene 139:185-191(1994) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-50.
[11]	"Binding of tissue inhibitor of metalloproteinases 2 to two distinct sites on human 72-kDa gelatinase. Identification of a stabilization site." Howard E.W., Banda M.J. J. Biol. Chem. 266:17972-17977(1991) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH MMP2.
[12]	"Human cervical tumor cell (SiHa) surface alphavbeta3 integrin receptor has associated matrix metalloproteinase (MMP-2) activity." Chattopadhyay N., Mitra A., Frei E., Chatterjee A. J. Cancer Res. Clin. Oncol. 127:653-658(2001) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH MMP2, FUNCTION.
[13]	"Solution structure of the active domain of tissue inhibitor of metalloproteinases-2. A new member of the OB fold protein family." Williamson R.A., Martorell G., Carr M.D., Murphy G., Docherty A.J.P., Freedman R.B., Feeney J. Biochemistry 33:11745-11759(1994) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 27-153.
[14]	"High resolution structure of the N-terminal domain of tissue inhibitor of metalloproteinases-2 and characterization of its interaction site with matrix metalloproteinase-3." Muskett F.W., Frenkiel T.A., Feeney J., Freedman R.B., Carr M.D., Williamson R.A. J. Biol. Chem. 273:21736-21743(1998) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 27-153.
[15]	"Three-dimensional structure of human tissue inhibitor of metalloproteinases-2 at 2.1-A resolution." Tuuttila A., Morgunova E., Bergmann U., Lindqvist Y., Maskos K., Fernandez-Catalan C., Bode W., Tryggvason K., Schneider G. J. Mol. Biol. 284:1133-1140(1998) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF 27-220.
[16]	"Structural insight into the complex formation of latent matrix metalloproteinase 2 with tissue inhibitor of metalloproteinase 2." Morgunova E., Tuuttila A., Bergmann U., Tryggvason K. Proc. Natl. Acad. Sci. U.S.A. 99:7414-7419(2002) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (3.10 ANGSTROMS) IN COMPLEX WITH MMP-2, DISULFIDE BOND.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

J05593 mRNA. Translation: AAA61186.1.
S48568 mRNA. Translation: AAB19474.1.
U44385 , U44381, U44382, U44383 Genomic DNA. Translation: AAC50729.1.
M32304 mRNA. Translation: AAA59581.1.
BC052605 mRNA. Translation: AAH52605.1.
BC071586 mRNA. Translation: AAH71586.1.
X54533 mRNA. Translation: CAA38400.1.
S68860 Genomic DNA. Translation: AAD14025.1.

IPI

IPI00027166.

PIR

A37128.
I53729.

RefSeq

NP_003246.1. NM_003255.4.

UniGene

Hs.633514.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1BR9	X-ray	2.10	A	27-220	[»]
1GXD	X-ray	3.10	C/D	27-220	[»]
2TMP	NMR	-	A	27-153	[»]

ProteinModelPortal

P16035.

ModBase

Search...

Protein-protein interaction databases

IntAct

P16035. 1 interaction.

STRING

9606.ENSP00000262768.

Protein family/group databases

MEROPS

I35.002.

Polymorphism databases

DMDM

135854.

2D gel databases

DOSAC-COBS-2DPAGE

P16035.

Proteomic databases

PaxDb

P16035.

PeptideAtlas

P16035.

PRIDE

P16035.

Protocols and materials databases

DNASU

7077.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000262768; ENSP00000262768; ENSG00000035862.

GeneID

7077.

KEGG

hsa:7077.

UCSC

uc002jwe.3. human.

Organism-specific databases

CTD

7077.

GeneCards

GC17M076850.

HGNC

HGNC:11821. TIMP2.

HPA

CAB010203.

MIM

188825. gene.

neXtProt

NX_P16035.

PharmGKB

PA36527.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG243625.

HOGENOM

HOG000285981.

HOVERGEN

HBG068749.

InParanoid

P16035.

OMA

KMFKGPE.

OrthoDB

EOG4XPQGS.

PhylomeDB

P16035.

Enzyme and pathway databases

Reactome

REACT_118779. Extracellular matrix organization.

Gene expression databases

ArrayExpress

P16035.

Bgee

P16035.

CleanEx

HS_TIMP2.

Genevestigator

P16035.

GermOnline

ENSG00000035862. Homo sapiens.

Family and domain databases

InterPro

IPR001134. Netrin_domain.
IPR001820. Prot_inh_TIMP.
IPR008993. TIMP-like_OB-fold.
IPR015613. TIMP2.
[Graphical view]

PANTHER

PTHR11844. PTHR11844. 1 hit.
PTHR11844:SF7. PTHR11844:SF7. 1 hit.

Pfam

PF00965. TIMP. 1 hit.
[Graphical view]

SMART

SM00206. NTR. 1 hit.
[Graphical view]

SUPFAM

SSF50242. TIMP_like. 1 hit.

PROSITE

PS50189. NTR. 1 hit.
PS00288. TIMP. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

ChiTaRS

TIMP2. human.

EvolutionaryTrace

P16035.

GenomeRNAi

7077.

NextBio

27679.

SOURCE

Search...

Entry information

Entry name

TIMP2_HUMAN

Accession

Primary (citable) accession number: P16035
Secondary accession number(s): Q16121, Q93006, Q9UDF7

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 1, 1990
Last sequence update:	November 1, 1990
Last modified:	May 1, 2013
This is version 144 of the entry and version 2 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.