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P16035 (TIMP2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 151. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (4) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Metalloproteinase inhibitor 2
Alternative name(s):
CSC-21K
Tissue inhibitor of metalloproteinases 2
Short name=TIMP-2
Gene names
Name:TIMP2
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length220 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence 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 componentSecreted
   DomainSignal
   LigandMetal-binding
Zinc
   Molecular functionMetalloenzyme inhibitor
Metalloprotease inhibitor
Protease inhibitor
   PTMDisulfide bond
   Technical term3D-structure
Complete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processaging

Inferred from electronic annotation. Source: Ensembl

cellular response to organic substance

Inferred from electronic annotation. Source: Ensembl

central nervous system development

Inferred from electronic annotation. Source: Ensembl

extracellular matrix disassembly

Traceable author statement. Source: Reactome

extracellular matrix organization

Traceable author statement. Source: Reactome

negative regulation of Ras protein signal transduction

Inferred from electronic annotation. Source: Ensembl

negative regulation of cell proliferation

Inferred from electronic annotation. Source: Ensembl

negative regulation of endopeptidase activity

Traceable author statement Ref.3. Source: GOC

negative regulation of mitotic cell cycle

Inferred from electronic annotation. Source: Ensembl

negative regulation of proteolysis

Inferred from electronic annotation. Source: Ensembl

positive regulation of MAPK cascade

Inferred from electronic annotation. Source: Ensembl

positive regulation of adenylate cyclase activity

Inferred from electronic annotation. Source: Ensembl

positive regulation of neuron differentiation

Inferred from electronic annotation. Source: Ensembl

regulation of Rap protein signal transduction

Inferred from electronic annotation. Source: Ensembl

response to cytokine

Inferred from electronic annotation. Source: Ensembl

response to drug

Inferred from electronic annotation. Source: Ensembl

   Cellular_componentbasement membrane

Inferred from electronic annotation. Source: Ensembl

cell surface

Inferred from electronic annotation. Source: Ensembl

extracellular region

Traceable author statement. Source: Reactome

extracellular space

Inferred from electronic annotation. Source: Ensembl

growth cone

Inferred from electronic annotation. Source: Ensembl

neuronal cell body

Inferred from electronic annotation. Source: Ensembl

   Molecular_functionenzyme activator activity

Inferred from electronic annotation. Source: Ensembl

metal ion binding

Inferred from electronic annotation. Source: UniProtKB-KW

metalloendopeptidase inhibitor activity

Traceable author statement Ref.3. Source: ProtInc

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

MMP14P502812EBI-1033507,EBI-992788

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 2626 Ref.6 Ref.7 Ref.9
Chain27 – 220194Metalloproteinase inhibitor 2
PRO_0000034335

Regions

Domain27 – 152126NTR
Region27 – 315Involved in metalloproteinase-binding
Region95 – 962Involved in metalloproteinase-binding

Sites

Metal binding271Zinc; via amino nitrogen and carbonyl oxygen; shared with metalloproteinase partner By similarity

Amino acid modifications

Disulfide bond27 ↔ 98 Ref.16
Disulfide bond29 ↔ 127 Ref.16
Disulfide bond39 ↔ 152 Ref.16
Disulfide bond154 ↔ 201 Ref.16
Disulfide bond159 ↔ 164 Ref.16
Disulfide bond172 ↔ 193 Ref.16

Experimental info

Sequence conflict17 – 193LAT → P in AAC50729. Ref.3
Sequence conflict44 – 507VIRAKAV → GKESGDP Ref.10
Sequence conflict781M → K AA sequence Ref.6
Sequence conflict781M → K AA sequence Ref.7
Sequence conflict821P → I AA sequence Ref.6
Sequence conflict821P → I AA sequence Ref.7
Sequence conflict961A → V in CAA38400. Ref.5
Sequence conflict1011S → E AA sequence Ref.6
Sequence conflict1011S → E AA sequence Ref.7
Sequence conflict1181Missing AA sequence Ref.6
Sequence conflict1181Missing AA sequence Ref.7
Sequence conflict1221M → R AA sequence Ref.6
Sequence conflict1221M → R AA sequence Ref.7
Sequence conflict1501M → Q AA sequence Ref.6
Sequence conflict1501M → Q AA sequence Ref.7
Sequence conflict1751M → T AA sequence Ref.6
Sequence conflict1751M → T AA sequence Ref.7

Secondary structure

......................................... 220
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
P16035 [UniParc].

Last modified November 1, 1990. Version 2.
Checksum: 603E5B1C9F94735D

FASTA22024,399
        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 

« Hide

References

« Hide '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.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
J05593 mRNA. Translation: AAA61186.1.
S48568 mRNA. Translation: AAB19474.1.
U44385 expand/collapse EMBL AC list , 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.
PIRA37128.
I53729.
RefSeqNP_003246.1. NM_003255.4.
UniGeneHs.633514.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1BR9X-ray2.10A27-220[»]
1GXDX-ray3.10C/D27-220[»]
2TMPNMR-A27-153[»]
4ILWX-ray2.10A/B27-220[»]
ProteinModelPortalP16035.
SMRP16035. Positions 27-208.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid112933. 5 interactions.
IntActP16035. 2 interactions.
STRING9606.ENSP00000262768.

Protein family/group databases

MEROPSI35.002.

Polymorphism databases

DMDM135854.

2D gel databases

DOSAC-COBS-2DPAGEP16035.

Proteomic databases

PaxDbP16035.
PeptideAtlasP16035.
PRIDEP16035.

Protocols and materials databases

DNASU7077.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000262768; ENSP00000262768; ENSG00000035862.
GeneID7077.
KEGGhsa:7077.
UCSCuc002jwe.3. human.

Organism-specific databases

CTD7077.
GeneCardsGC17M076850.
HGNCHGNC:11821. TIMP2.
HPACAB010203.
MIM188825. gene.
neXtProtNX_P16035.
PharmGKBPA36527.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG243625.
HOGENOMHOG000285981.
HOVERGENHBG068749.
InParanoidP16035.
OMAKMFKGPE.
OrthoDBEOG79GT74.
PhylomeDBP16035.
TreeFamTF317409.

Enzyme and pathway databases

ReactomeREACT_118779. Extracellular matrix organization.

Gene expression databases

ArrayExpressP16035.
BgeeP16035.
CleanExHS_TIMP2.
GenevestigatorP16035.

Family and domain databases

Gene3D3.90.370.10. 1 hit.
InterProIPR001134. Netrin_domain.
IPR001820. Prot_inh_TIMP.
IPR008993. TIMP-like_OB-fold.
IPR015613. TIMP2.
IPR027465. TIMP_C_dom.
[Graphical view]
PANTHERPTHR11844. PTHR11844. 1 hit.
PTHR11844:SF7. PTHR11844:SF7. 1 hit.
PfamPF00965. TIMP. 1 hit.
[Graphical view]
SMARTSM00206. NTR. 1 hit.
[Graphical view]
SUPFAMSSF50242. SSF50242. 1 hit.
PROSITEPS50189. NTR. 1 hit.
PS00288. TIMP. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSTIMP2. human.
EvolutionaryTraceP16035.
GeneWikiTIMP2.
GenomeRNAi7077.
NextBio27679.
PROP16035.
SOURCESearch...

Entry information

Entry nameTIMP2_HUMAN
AccessionPrimary (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: April 16, 2014
This is version 151 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human chromosome 17

Human chromosome 17: entries, gene names and cross-references to MIM