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P16035

- TIMP2_HUMAN

UniProt

P16035 - TIMP2_HUMAN

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Protein

Metalloproteinase inhibitor 2

Gene

TIMP2

Organism
Homo sapiens (Human)
Status
Reviewed - 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

  1. enzyme activator activity Source: Ensembl
  2. metal ion binding Source: UniProtKB-KW
  3. metalloendopeptidase inhibitor activity Source: ProtInc

GO - Biological processi

  1. aging Source: Ensembl
  2. cellular response to organic substance Source: Ensembl
  3. central nervous system development Source: Ensembl
  4. extracellular matrix disassembly Source: Reactome
  5. extracellular matrix organization Source: Reactome
  6. negative regulation of cell proliferation Source: Ensembl
  7. negative regulation of endopeptidase activity Source: GOC
  8. negative regulation of mitotic cell cycle Source: Ensembl
  9. negative regulation of proteolysis Source: Ensembl
  10. negative regulation of Ras protein signal transduction Source: Ensembl
  11. positive regulation of adenylate cyclase activity Source: Ensembl
  12. positive regulation of MAPK cascade Source: Ensembl
  13. positive regulation of neuron differentiation Source: Ensembl
  14. regulation of Rap protein signal transduction Source: Ensembl
  15. response to cytokine Source: Ensembl
  16. response to drug Source: Ensembl
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: Chromosome 17

Organism-specific databases

HGNCiHGNC:11821. TIMP2.

Subcellular locationi

GO - Cellular componenti

  1. basement membrane Source: Ensembl
  2. cell surface Source: Ensembl
  3. extracellular region Source: Reactome
  4. extracellular space Source: Ensembl
  5. extracellular vesicular exosome Source: UniProt
  6. growth cone Source: Ensembl
  7. neuronal cell body Source: Ensembl
Complete GO annotation...

Keywords - Cellular componenti

Secreted

Pathology & Biotechi

Organism-specific databases

PharmGKBiPA36527.

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 ↔ 981 PublicationPROSITE-ProRule annotation
Disulfide bondi29 ↔ 1271 PublicationPROSITE-ProRule annotation
Disulfide bondi39 ↔ 1521 PublicationPROSITE-ProRule annotation
Disulfide bondi154 ↔ 2011 PublicationPROSITE-ProRule annotation
Disulfide bondi159 ↔ 1641 PublicationPROSITE-ProRule annotation
Disulfide bondi172 ↔ 1931 PublicationPROSITE-ProRule annotation

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.
GenevestigatoriP16035.

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 – 407
Beta strandi41 – 5919
Beta strandi61 – 633
Beta strandi65 – 8117
Beta strandi88 – 914
Helixi95 – 973
Turni104 – 1074
Beta strandi109 – 11810
Beta strandi121 – 1233
Beta strandi130 – 1323
Helixi133 – 1353
Helixi138 – 1436
Turni144 – 1485
Helixi149 – 1513
Beta strandi154 – 1585
Beta strandi161 – 1633
Beta strandi171 – 1744
Helixi176 – 1805
Beta strandi181 – 1855
Helixi186 – 1905
Beta strandi192 – 1954
Beta strandi197 – 1993
Beta strandi201 – 2044

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
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.
OMAiSTTHRYM.
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.
[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. 1 PublicationCurated
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:
EMBL
GenBank
DDBJ
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.

Polymorphism databases

DMDMi135854.

Cross-referencesi

Web resourcesi

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
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 .
CCDSi CCDS11758.1.
PIRi A37128.
I53729.
RefSeqi NP_003246.1. NM_003255.4.
UniGenei Hs.633514.

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
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 [» ]
4ILW X-ray 2.10 A/B 27-220 [» ]
ProteinModelPortali P16035.
SMRi P16035. Positions 27-208.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 112933. 8 interactions.
IntActi P16035. 2 interactions.
STRINGi 9606.ENSP00000262768.

Protein family/group databases

MEROPSi I35.002.

Polymorphism databases

DMDMi 135854.

2D gel databases

DOSAC-COBS-2DPAGE P16035.

Proteomic databases

MaxQBi P16035.
PaxDbi P16035.
PeptideAtlasi P16035.
PRIDEi P16035.

Protocols and materials databases

DNASUi 7077.
Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENST00000262768 ; ENSP00000262768 ; ENSG00000035862 .
GeneIDi 7077.
KEGGi hsa:7077.
UCSCi uc002jwe.3. human.

Organism-specific databases

CTDi 7077.
GeneCardsi GC17M076850.
HGNCi HGNC:11821. TIMP2.
HPAi CAB010203.
MIMi 188825. gene.
neXtProti NX_P16035.
PharmGKBi PA36527.
GenAtlasi Search...

Phylogenomic databases

eggNOGi NOG243625.
GeneTreei ENSGT00390000004555.
HOGENOMi HOG000285981.
HOVERGENi HBG068749.
InParanoidi P16035.
OMAi STTHRYM.
OrthoDBi EOG79GT74.
PhylomeDBi P16035.
TreeFami TF317409.

Enzyme and pathway databases

Reactomei REACT_118682. Activation of Matrix Metalloproteinases.

Miscellaneous databases

ChiTaRSi TIMP2. human.
EvolutionaryTracei P16035.
GeneWikii TIMP2.
GenomeRNAii 7077.
NextBioi 27679.
PROi P16035.
SOURCEi Search...

Gene expression databases

Bgeei P16035.
CleanExi HS_TIMP2.
ExpressionAtlasi P16035. baseline and differential.
Genevestigatori P16035.

Family and domain databases

Gene3Di 3.90.370.10. 1 hit.
InterProi IPR001134. Netrin_domain.
IPR001820. Prot_inh_TIMP.
IPR008993. TIMP-like_OB-fold.
IPR015613. TIMP2.
IPR027465. TIMP_C_dom.
[Graphical view ]
PANTHERi PTHR11844. PTHR11844. 1 hit.
PTHR11844:SF7. PTHR11844:SF7. 1 hit.
Pfami PF00965. TIMP. 1 hit.
[Graphical view ]
SMARTi SM00206. NTR. 1 hit.
[Graphical view ]
SUPFAMi SSF50242. SSF50242. 1 hit.
PROSITEi PS50189. NTR. 1 hit.
PS00288. TIMP. 1 hit.
[Graphical view ]
ProtoNeti Search...

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: October 29, 2014
This is version 157 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