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P16035

- TIMP2_HUMAN

UniProt

P16035 - TIMP2_HUMAN

Protein

Metalloproteinase inhibitor 2

Gene

TIMP2

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 156 (01 Oct 2014)
      Sequence version 2 (01 Nov 1990)
      Previous versions | rss
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    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
    4. protein binding Source: IntAct

    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

    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

    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

    ArrayExpressiP16035.
    BgeeiP16035.
    CleanExiHS_TIMP2.
    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. 5 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.
    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

    MGAAARTLRL ALGLLLLATL LRPADACSCS PVHPQQAFCN ADVVIRAKAV    50
    SEKEVDSGND IYGNPIKRIQ YEIKQIKMFK GPEKDIEFIY TAPSSAVCGV 100
    SLDVGGKKEY LIAGKAEGDG KMHITLCDFI VPWDTLSTTQ KKSLNHRYQM 150
    GCECKITRCP MIPCYISSPD ECLWMDWVTE KNINGHQAKF FACIKRSDGS 200
    CAWYRGAAPP KQEFLDIEDP 220
    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. 5 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.
    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

    ArrayExpressi P16035.
    Bgeei P16035.
    CleanExi HS_TIMP2.
    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

    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 1, 2014
    This is version 156 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