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Protein

Metalloproteinase inhibitor 2

Gene

TIMP2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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-19.3 Publications

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Metal bindingi27 – 271Zinc; via amino nitrogen and carbonyl oxygen; shared with metalloproteinase partnerBy similarity

GO - Molecular functioni

  • enzyme activator activity Source: Ensembl
  • metal ion binding Source: UniProtKB-KW
  • metalloendopeptidase inhibitor activity Source: ProtInc
  • protease binding Source: GO_Central

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Metalloenzyme inhibitor, Metalloprotease inhibitor, Protease inhibitor

Keywords - Ligandi

Metal-binding, Zinc

Enzyme and pathway databases

ReactomeiREACT_118682. Activation of Matrix Metalloproteinases.

Protein family/group databases

MEROPSiI35.002.

Names & Taxonomyi

Protein namesi
Recommended name:
Metalloproteinase inhibitor 2
Alternative name(s):
CSC-21K
Tissue inhibitor of metalloproteinases 2
Short name:
TIMP-2
Gene namesi
Name:TIMP2
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640 Componenti: Chromosome 17

Organism-specific databases

HGNCiHGNC:11821. TIMP2.

Subcellular locationi

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Secreted

Pathology & Biotechi

Organism-specific databases

PharmGKBiPA36527.

Polymorphism and mutation databases

BioMutaiTIMP2.
DMDMi135854.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 26263 PublicationsAdd
BLAST
Chaini27 – 220194Metalloproteinase inhibitor 2PRO_0000034335Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Disulfide bondi27 ↔ 98PROSITE-ProRule annotation1 Publication
Disulfide bondi29 ↔ 127PROSITE-ProRule annotation1 Publication
Disulfide bondi39 ↔ 152PROSITE-ProRule annotation1 Publication
Disulfide bondi154 ↔ 201PROSITE-ProRule annotation1 Publication
Disulfide bondi159 ↔ 164PROSITE-ProRule annotation1 Publication
Disulfide bondi172 ↔ 193PROSITE-ProRule annotation1 Publication

Post-translational modificationi

The activity of TIMP2 is dependent on the presence of disulfide bonds.

Keywords - PTMi

Disulfide bond

Proteomic databases

MaxQBiP16035.
PaxDbiP16035.
PeptideAtlasiP16035.
PRIDEiP16035.

2D gel databases

DOSAC-COBS-2DPAGEP16035.

Expressioni

Inductioni

Down-regulated by TGFB1.1 Publication

Gene expression databases

BgeeiP16035.
CleanExiHS_TIMP2.
ExpressionAtlasiP16035. baseline and differential.
GenevisibleiP16035. HS.

Organism-specific databases

HPAiCAB010203.

Interactioni

Subunit structurei

Interacts (via the C-terminal) with MMP2 (via the C-terminal PEX domain); the interaction inhibits the MMP2 activity.3 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
MMP14P502812EBI-1033507,EBI-992788

Protein-protein interaction databases

BioGridi112933. 8 interactions.
IntActiP16035. 2 interactions.
STRINGi9606.ENSP00000262768.

Structurei

Secondary structure

1
220
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Helixi34 – 407Combined sources
Beta strandi41 – 5919Combined sources
Beta strandi61 – 633Combined sources
Beta strandi65 – 8117Combined sources
Beta strandi88 – 914Combined sources
Helixi95 – 973Combined sources
Turni104 – 1074Combined sources
Beta strandi109 – 11810Combined sources
Beta strandi121 – 1233Combined sources
Beta strandi130 – 1323Combined sources
Helixi133 – 1353Combined sources
Helixi138 – 1436Combined sources
Turni144 – 1485Combined sources
Helixi149 – 1513Combined sources
Beta strandi154 – 1585Combined sources
Beta strandi161 – 1633Combined sources
Beta strandi171 – 1744Combined sources
Helixi176 – 1805Combined sources
Beta strandi181 – 1855Combined sources
Helixi186 – 1905Combined sources
Beta strandi192 – 1954Combined sources
Beta strandi197 – 1993Combined sources
Beta strandi201 – 2044Combined sources

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
1BR9X-ray2.10A27-220[»]
1GXDX-ray3.10C/D27-220[»]
2TMPNMR-A27-153[»]
4ILWX-ray2.10A/B27-220[»]
ProteinModelPortaliP16035.
SMRiP16035. Positions 27-208.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP16035.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini27 – 152126NTRPROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni27 – 315Involved in metalloproteinase-binding
Regioni95 – 962Involved in metalloproteinase-binding

Sequence similaritiesi

Contains 1 NTR domain.PROSITE-ProRule annotation

Keywords - Domaini

Signal

Phylogenomic databases

eggNOGiNOG243625.
GeneTreeiENSGT00390000004555.
HOGENOMiHOG000285981.
HOVERGENiHBG068749.
InParanoidiP16035.
OMAiKMFKGPE.
OrthoDBiEOG79GT74.
PhylomeDBiP16035.
TreeFamiTF317409.

Family and domain databases

Gene3Di3.90.370.10. 1 hit.
InterProiIPR001134. Netrin_domain.
IPR001820. Prot_inh_TIMP.
IPR008993. TIMP-like_OB-fold.
IPR015613. TIMP2.
IPR027465. TIMP_C_dom.
IPR030490. TIMP_CS.
[Graphical view]
PANTHERiPTHR11844. PTHR11844. 1 hit.
PTHR11844:SF7. PTHR11844:SF7. 1 hit.
PfamiPF00965. TIMP. 1 hit.
[Graphical view]
SMARTiSM00206. NTR. 1 hit.
[Graphical view]
SUPFAMiSSF50242. SSF50242. 1 hit.
PROSITEiPS50189. NTR. 1 hit.
PS00288. TIMP. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

P16035-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MGAAARTLRL ALGLLLLATL LRPADACSCS PVHPQQAFCN ADVVIRAKAV
60 70 80 90 100
SEKEVDSGND IYGNPIKRIQ YEIKQIKMFK GPEKDIEFIY TAPSSAVCGV
110 120 130 140 150
SLDVGGKKEY LIAGKAEGDG KMHITLCDFI VPWDTLSTTQ KKSLNHRYQM
160 170 180 190 200
GCECKITRCP MIPCYISSPD ECLWMDWVTE KNINGHQAKF FACIKRSDGS
210 220
CAWYRGAAPP KQEFLDIEDP
Length:220
Mass (Da):24,399
Last modified:November 1, 1990 - v2
Checksum:i603E5B1C9F94735D
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti17 – 193LAT → P in AAC50729 (PubMed:8810321).Curated
Sequence conflicti44 – 507VIRAKAV → GKESGDP (PubMed:8112602).Curated
Sequence conflicti78 – 781M → K AA sequence (PubMed:2793861).Curated
Sequence conflicti78 – 781M → K AA sequence (PubMed:1480041).Curated
Sequence conflicti82 – 821P → I AA sequence (PubMed:2793861).Curated
Sequence conflicti82 – 821P → I AA sequence (PubMed:1480041).Curated
Sequence conflicti96 – 961A → V in CAA38400 (Ref. 5) Curated
Sequence conflicti101 – 1011S → E AA sequence (PubMed:2793861).Curated
Sequence conflicti101 – 1011S → E AA sequence (PubMed:1480041).Curated
Sequence conflicti118 – 1181Missing AA sequence (PubMed:2793861).Curated
Sequence conflicti118 – 1181Missing AA sequence (PubMed:1480041).Curated
Sequence conflicti122 – 1221M → R AA sequence (PubMed:2793861).Curated
Sequence conflicti122 – 1221M → R AA sequence (PubMed:1480041).Curated
Sequence conflicti150 – 1501M → Q AA sequence (PubMed:2793861).Curated
Sequence conflicti150 – 1501M → Q AA sequence (PubMed:1480041).Curated
Sequence conflicti175 – 1751M → T AA sequence (PubMed:2793861).Curated
Sequence conflicti175 – 1751M → T AA sequence (PubMed:1480041).Curated

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
CCDSiCCDS11758.1.
PIRiA37128.
I53729.
RefSeqiNP_003246.1. NM_003255.4.
UniGeneiHs.633514.

Genome annotation databases

EnsembliENST00000262768; ENSP00000262768; ENSG00000035862.
GeneIDi7077.
KEGGihsa:7077.
UCSCiuc002jwe.3. human.

Cross-referencesi

Web resourcesi

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
CCDSiCCDS11758.1.
PIRiA37128.
I53729.
RefSeqiNP_003246.1. NM_003255.4.
UniGeneiHs.633514.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
1BR9X-ray2.10A27-220[»]
1GXDX-ray3.10C/D27-220[»]
2TMPNMR-A27-153[»]
4ILWX-ray2.10A/B27-220[»]
ProteinModelPortaliP16035.
SMRiP16035. Positions 27-208.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi112933. 8 interactions.
IntActiP16035. 2 interactions.
STRINGi9606.ENSP00000262768.

Protein family/group databases

MEROPSiI35.002.

Polymorphism and mutation databases

BioMutaiTIMP2.
DMDMi135854.

2D gel databases

DOSAC-COBS-2DPAGEP16035.

Proteomic databases

MaxQBiP16035.
PaxDbiP16035.
PeptideAtlasiP16035.
PRIDEiP16035.

Protocols and materials databases

DNASUi7077.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000262768; ENSP00000262768; ENSG00000035862.
GeneIDi7077.
KEGGihsa:7077.
UCSCiuc002jwe.3. human.

Organism-specific databases

CTDi7077.
GeneCardsiGC17M076850.
HGNCiHGNC:11821. TIMP2.
HPAiCAB010203.
MIMi188825. gene.
neXtProtiNX_P16035.
PharmGKBiPA36527.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiNOG243625.
GeneTreeiENSGT00390000004555.
HOGENOMiHOG000285981.
HOVERGENiHBG068749.
InParanoidiP16035.
OMAiKMFKGPE.
OrthoDBiEOG79GT74.
PhylomeDBiP16035.
TreeFamiTF317409.

Enzyme and pathway databases

ReactomeiREACT_118682. Activation of Matrix Metalloproteinases.

Miscellaneous databases

ChiTaRSiTIMP2. human.
EvolutionaryTraceiP16035.
GeneWikiiTIMP2.
GenomeRNAii7077.
NextBioi27679.
PROiP16035.
SOURCEiSearch...

Gene expression databases

BgeeiP16035.
CleanExiHS_TIMP2.
ExpressionAtlasiP16035. baseline and differential.
GenevisibleiP16035. HS.

Family and domain databases

Gene3Di3.90.370.10. 1 hit.
InterProiIPR001134. Netrin_domain.
IPR001820. Prot_inh_TIMP.
IPR008993. TIMP-like_OB-fold.
IPR015613. TIMP2.
IPR027465. TIMP_C_dom.
IPR030490. TIMP_CS.
[Graphical view]
PANTHERiPTHR11844. PTHR11844. 1 hit.
PTHR11844:SF7. PTHR11844:SF7. 1 hit.
PfamiPF00965. TIMP. 1 hit.
[Graphical view]
SMARTiSM00206. NTR. 1 hit.
[Graphical view]
SUPFAMiSSF50242. SSF50242. 1 hit.
PROSITEiPS50189. NTR. 1 hit.
PS00288. TIMP. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  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.

Entry informationi

Entry nameiTIMP2_HUMAN
AccessioniPrimary (citable) accession number: P16035
Secondary accession number(s): Q16121, Q93006, Q9UDF7
Entry historyi
Integrated into UniProtKB/Swiss-Prot: April 1, 1990
Last sequence update: November 1, 1990
Last modified: June 24, 2015
This is version 164 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 17
    Human chromosome 17: entries, gene names and cross-references to MIM
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  4. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.