TIMP2_HUMAN
ID TIMP2_HUMAN Reviewed; 220 AA.
AC P16035; Q16121; Q93006; Q9UDF7;
DT 01-APR-1990, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1990, sequence version 2.
DT 03-AUG-2022, entry version 212.
DE RecName: Full=Metalloproteinase inhibitor 2;
DE AltName: Full=CSC-21K;
DE AltName: Full=Tissue inhibitor of metalloproteinases 2;
DE Short=TIMP-2;
DE Flags: Precursor;
GN Name=TIMP2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND INDUCTION.
RX PubMed=2380196; DOI=10.1016/s0021-9258(18)77438-3;
RA Stetler-Stevenson W.G., Brown P.D., Onisto M., Levy A.T., Liotta L.A.;
RT "Tissue inhibitor of metalloproteinases-2 (TIMP-2) mRNA expression in tumor
RT cell lines and human tumor tissues.";
RL J. Biol. Chem. 265:13933-13938(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2157214; DOI=10.1073/pnas.87.7.2800;
RA Boone T.C., Johnson M.J., de Clerck Y.A., Langley K.E.;
RT "cDNA cloning and expression of a metalloproteinase inhibitor related to
RT tissue inhibitor of metalloproteinases.";
RL Proc. Natl. Acad. Sci. U.S.A. 87:2800-2804(1990).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Placenta;
RX PubMed=8810321; DOI=10.1074/jbc.271.41.25498;
RA Hammani K., Blakis A., Morsette D., Bowcock A., Schmutte C., Henriet P.,
RA Declerck Y.A.;
RT "Structure and characterization of the human tissue inhibitor of
RT metalloproteinases-2 gene.";
RL J. Biol. Chem. 271:25498-25505(1996).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Placenta, and Skin;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE OF 30-214.
RA Malik K., Sejima H., Aoki T., Iwata K.;
RL Submitted (AUG-1990) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP PROTEIN SEQUENCE OF 27-219, AND FUNCTION.
RX PubMed=2793861; DOI=10.1016/s0021-9258(18)71503-2;
RA Stetler-Stevenson W.G., Krutzsch H.C., Liotta L.A.;
RT "Tissue inhibitor of metalloproteinase (TIMP-2). A new member of the
RT metalloproteinase inhibitor family.";
RL J. Biol. Chem. 264:17374-17378(1989).
RN [7]
RP PROTEIN SEQUENCE OF 27-219.
RX PubMed=1480041;
RA Stetler-Stevenson W.G., Krutzsch H.C., Liotta L.A.;
RT "TIMP-2: identification and characterization of a new member of the
RT metalloproteinase inhibitor family.";
RL Matrix Suppl. 1:299-306(1992).
RN [8]
RP PROTEIN SEQUENCE OF 30-51; 124-141 AND 159-173, AND FUNCTION.
RX PubMed=2554304; DOI=10.1073/pnas.86.21.8207;
RA Goldberg G.I., Marmer B.L., Grant G.A., Eisen A.Z., Wilhelm S., He C.;
RT "Human 72-kilodalton type IV collagenase forms a complex with a tissue
RT inhibitor of metalloproteases designated TIMP-2.";
RL Proc. Natl. Acad. Sci. U.S.A. 86:8207-8211(1989).
RN [9]
RP PROTEIN SEQUENCE OF 27-41.
RC TISSUE=Synovial fluid;
RX PubMed=1730286; DOI=10.1016/0014-5793(92)80393-u;
RA Osthues A., Knaueper V., Oberhoff R., Reinke H., Tschesche H.;
RT "Isolation and characterization of tissue inhibitors of metalloproteinases
RT (TIMP-1 and TIMP-2) from human rheumatoid synovial fluid.";
RL FEBS Lett. 296:16-20(1992).
RN [10]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-50.
RX PubMed=8112602; DOI=10.1016/0378-1119(94)90753-6;
RA de Clerck Y.A., Darville M.I., Eeckhout Y., Rousseau G.G.;
RT "Characterization of the promoter of the gene encoding human tissue
RT inhibitor of metalloproteinases-2 (TIMP-2).";
RL Gene 139:185-191(1994).
RN [11]
RP INTERACTION WITH MMP2.
RX PubMed=1655733; DOI=10.1016/s0021-9258(18)55224-8;
RA Howard E.W., Banda M.J.;
RT "Binding of tissue inhibitor of metalloproteinases 2 to two distinct sites
RT on human 72-kDa gelatinase. Identification of a stabilization site.";
RL J. Biol. Chem. 266:17972-17977(1991).
RN [12]
RP INTERACTION WITH MMP2, AND FUNCTION.
RX PubMed=11710594; DOI=10.1007/s004320100271;
RA Chattopadhyay N., Mitra A., Frei E., Chatterjee A.;
RT "Human cervical tumor cell (SiHa) surface alphavbeta3 integrin receptor has
RT associated matrix metalloproteinase (MMP-2) activity.";
RL J. Cancer Res. Clin. Oncol. 127:653-658(2001).
RN [13]
RP STRUCTURE BY NMR OF 27-153.
RX PubMed=7918391; DOI=10.1021/bi00205a010;
RA Williamson R.A., Martorell G., Carr M.D., Murphy G., Docherty A.J.P.,
RA Freedman R.B., Feeney J.;
RT "Solution structure of the active domain of tissue inhibitor of
RT metalloproteinases-2. A new member of the OB fold protein family.";
RL Biochemistry 33:11745-11759(1994).
RN [14]
RP STRUCTURE BY NMR OF 27-153.
RX PubMed=9705310; DOI=10.1074/jbc.273.34.21736;
RA Muskett F.W., Frenkiel T.A., Feeney J., Freedman R.B., Carr M.D.,
RA Williamson R.A.;
RT "High resolution structure of the N-terminal domain of tissue inhibitor of
RT metalloproteinases-2 and characterization of its interaction site with
RT matrix metalloproteinase-3.";
RL J. Biol. Chem. 273:21736-21743(1998).
RN [15]
RP X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF 27-220.
RX PubMed=9837731; DOI=10.1006/jmbi.1998.2223;
RA Tuuttila A., Morgunova E., Bergmann U., Lindqvist Y., Maskos K.,
RA Fernandez-Catalan C., Bode W., Tryggvason K., Schneider G.;
RT "Three-dimensional structure of human tissue inhibitor of
RT metalloproteinases-2 at 2.1-A resolution.";
RL J. Mol. Biol. 284:1133-1140(1998).
RN [16]
RP X-RAY CRYSTALLOGRAPHY (3.10 ANGSTROMS) IN COMPLEX WITH MMP-2, AND DISULFIDE
RP BOND.
RX PubMed=12032297; DOI=10.1073/pnas.102185399;
RA Morgunova E., Tuuttila A., Bergmann U., Tryggvason K.;
RT "Structural insight into the complex formation of latent matrix
RT metalloproteinase 2 with tissue inhibitor of metalloproteinase 2.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:7414-7419(2002).
RN [17]
RP X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF 27-220 IN COMPLEX WITH MMP10 AND
RP ZINC.
RX PubMed=24073280; DOI=10.1371/journal.pone.0075836;
RA Batra J., Soares A.S., Mehner C., Radisky E.S.;
RT "Matrix metalloproteinase-10/TIMP-2 structure and analyses define conserved
RT core interactions and diverse exosite interactions in MMP/TIMP complexes.";
RL PLoS ONE 8:E75836-E75836(2013).
CC -!- FUNCTION: Complexes with metalloproteinases (such as collagenases) and
CC irreversibly inactivates them by binding to their catalytic zinc
CC cofactor. Known to act on MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9,
CC MMP-10, MMP-13, MMP-14, MMP-15, MMP-16 and MMP-19.
CC {ECO:0000269|PubMed:11710594, ECO:0000269|PubMed:2554304,
CC ECO:0000269|PubMed:2793861}.
CC -!- SUBUNIT: Interacts (via the C-terminal) with MMP2 (via the C-terminal
CC PEX domain); the interaction inhibits the MMP2 activity.
CC {ECO:0000269|PubMed:11710594, ECO:0000269|PubMed:12032297,
CC ECO:0000269|PubMed:1655733}.
CC -!- INTERACTION:
CC P16035; P50281: MMP14; NbExp=2; IntAct=EBI-1033507, EBI-992788;
CC P16035; P08253: MMP2; NbExp=2; IntAct=EBI-1033507, EBI-1033518;
CC P16035; Q9UHD9: UBQLN2; NbExp=3; IntAct=EBI-1033507, EBI-947187;
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- INDUCTION: Down-regulated by TGFB1. {ECO:0000269|PubMed:2380196}.
CC -!- PTM: The activity of TIMP2 is dependent on the presence of disulfide
CC bonds.
CC -!- SIMILARITY: Belongs to the protease inhibitor I35 (TIMP) family.
CC {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/TIMP2ID42572ch17q25.html";
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DR EMBL; J05593; AAA61186.1; -; mRNA.
DR EMBL; S48568; AAB19474.1; -; mRNA.
DR EMBL; U44385; AAC50729.1; -; Genomic_DNA.
DR EMBL; U44381; AAC50729.1; JOINED; Genomic_DNA.
DR EMBL; U44382; AAC50729.1; JOINED; Genomic_DNA.
DR EMBL; U44383; AAC50729.1; JOINED; Genomic_DNA.
DR EMBL; M32304; AAA59581.1; -; mRNA.
DR EMBL; BC052605; AAH52605.1; -; mRNA.
DR EMBL; BC071586; AAH71586.1; -; mRNA.
DR EMBL; X54533; CAA38400.1; -; mRNA.
DR EMBL; S68860; AAD14025.1; -; Genomic_DNA.
DR CCDS; CCDS11758.1; -.
DR PIR; A37128; A37128.
DR PIR; I53729; I53729.
DR RefSeq; NP_003246.1; NM_003255.4.
DR PDB; 1BR9; X-ray; 2.10 A; A=27-220.
DR PDB; 1GXD; X-ray; 3.10 A; C/D=27-220.
DR PDB; 2TMP; NMR; -; A=27-153.
DR PDB; 4ILW; X-ray; 2.10 A; A/B=27-220.
DR PDBsum; 1BR9; -.
DR PDBsum; 1GXD; -.
DR PDBsum; 2TMP; -.
DR PDBsum; 4ILW; -.
DR AlphaFoldDB; P16035; -.
DR BMRB; P16035; -.
DR SMR; P16035; -.
DR BioGRID; 112933; 34.
DR IntAct; P16035; 7.
DR MINT; P16035; -.
DR STRING; 9606.ENSP00000262768; -.
DR MEROPS; I35.002; -.
DR iPTMnet; P16035; -.
DR PhosphoSitePlus; P16035; -.
DR BioMuta; TIMP2; -.
DR DMDM; 135854; -.
DR DOSAC-COBS-2DPAGE; P16035; -.
DR EPD; P16035; -.
DR jPOST; P16035; -.
DR MassIVE; P16035; -.
DR MaxQB; P16035; -.
DR PaxDb; P16035; -.
DR PeptideAtlas; P16035; -.
DR PRIDE; P16035; -.
DR ProteomicsDB; 53263; -.
DR TopDownProteomics; P16035; -.
DR Antibodypedia; 4126; 1250 antibodies from 44 providers.
DR DNASU; 7077; -.
DR Ensembl; ENST00000262768.11; ENSP00000262768.6; ENSG00000035862.12.
DR GeneID; 7077; -.
DR KEGG; hsa:7077; -.
DR MANE-Select; ENST00000262768.11; ENSP00000262768.6; NM_003255.5; NP_003246.1.
DR UCSC; uc002jwf.4; human.
DR CTD; 7077; -.
DR DisGeNET; 7077; -.
DR GeneCards; TIMP2; -.
DR HGNC; HGNC:11821; TIMP2.
DR HPA; ENSG00000035862; Tissue enhanced (ovary).
DR MIM; 188825; gene.
DR neXtProt; NX_P16035; -.
DR OpenTargets; ENSG00000035862; -.
DR PharmGKB; PA36527; -.
DR VEuPathDB; HostDB:ENSG00000035862; -.
DR eggNOG; KOG4745; Eukaryota.
DR GeneTree; ENSGT00940000158348; -.
DR InParanoid; P16035; -.
DR OMA; DHYACIK; -.
DR OrthoDB; 1122531at2759; -.
DR PhylomeDB; P16035; -.
DR TreeFam; TF317409; -.
DR BRENDA; 3.4.24.22; 2681.
DR PathwayCommons; P16035; -.
DR Reactome; R-HSA-1592389; Activation of Matrix Metalloproteinases.
DR Reactome; R-HSA-6798695; Neutrophil degranulation.
DR SignaLink; P16035; -.
DR SIGNOR; P16035; -.
DR BioGRID-ORCS; 7077; 18 hits in 1072 CRISPR screens.
DR ChiTaRS; TIMP2; human.
DR EvolutionaryTrace; P16035; -.
DR GeneWiki; TIMP2; -.
DR GenomeRNAi; 7077; -.
DR Pharos; P16035; Tbio.
DR PRO; PR:P16035; -.
DR Proteomes; UP000005640; Chromosome 17.
DR RNAct; P16035; protein.
DR Bgee; ENSG00000035862; Expressed in tendon of biceps brachii and 197 other tissues.
DR ExpressionAtlas; P16035; baseline and differential.
DR Genevisible; P16035; HS.
DR GO; GO:0062023; C:collagen-containing extracellular matrix; HDA:BHF-UCL.
DR GO; GO:0031012; C:extracellular matrix; IBA:GO_Central.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IBA:GO_Central.
DR GO; GO:1904813; C:ficolin-1-rich granule lumen; TAS:Reactome.
DR GO; GO:0035580; C:specific granule lumen; TAS:Reactome.
DR GO; GO:1904724; C:tertiary granule lumen; TAS:Reactome.
DR GO; GO:0008191; F:metalloendopeptidase inhibitor activity; IBA:GO_Central.
DR GO; GO:0030414; F:peptidase inhibitor activity; IDA:UniProtKB.
DR GO; GO:0002020; F:protease binding; IPI:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB.
DR GO; GO:0010951; P:negative regulation of endopeptidase activity; IBA:GO_Central.
DR GO; GO:0051045; P:negative regulation of membrane protein ectodomain proteolysis; IBA:GO_Central.
DR GO; GO:1905049; P:negative regulation of metallopeptidase activity; IDA:UniProtKB.
DR GO; GO:0034097; P:response to cytokine; IBA:GO_Central.
DR GO; GO:0009725; P:response to hormone; IBA:GO_Central.
DR GO; GO:0010033; P:response to organic substance; IBA:GO_Central.
DR Gene3D; 2.40.50.120; -; 1.
DR Gene3D; 3.90.370.10; -; 1.
DR InterPro; IPR001134; Netrin_domain.
DR InterPro; IPR001820; TIMP.
DR InterPro; IPR008993; TIMP-like_OB-fold.
DR InterPro; IPR015613; TIMP2.
DR InterPro; IPR027465; TIMP_C.
DR InterPro; IPR030490; TIMP_CS.
DR PANTHER; PTHR11844; PTHR11844; 1.
DR PANTHER; PTHR11844:SF24; PTHR11844:SF24; 1.
DR Pfam; PF00965; TIMP; 1.
DR SMART; SM00206; NTR; 1.
DR SUPFAM; SSF50242; SSF50242; 1.
DR PROSITE; PS50189; NTR; 1.
DR PROSITE; PS00288; TIMP; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Direct protein sequencing; Disulfide bond; Metal-binding;
KW Metalloenzyme inhibitor; Metalloprotease inhibitor; Protease inhibitor;
KW Reference proteome; Secreted; Signal; Zinc.
FT SIGNAL 1..26
FT /evidence="ECO:0000269|PubMed:1480041,
FT ECO:0000269|PubMed:1730286, ECO:0000269|PubMed:2793861"
FT CHAIN 27..220
FT /note="Metalloproteinase inhibitor 2"
FT /id="PRO_0000034335"
FT DOMAIN 27..152
FT /note="NTR"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00295"
FT REGION 27..30
FT /note="Involved in metalloproteinase-binding"
FT /evidence="ECO:0000269|PubMed:24073280,
FT ECO:0007744|PDB:4ILW"
FT REGION 95..96
FT /note="Involved in metalloproteinase-binding"
FT /evidence="ECO:0000269|PubMed:24073280,
FT ECO:0007744|PDB:4ILW"
FT BINDING 27
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="ligand shared with metalloproteinase partner"
FT /evidence="ECO:0000269|PubMed:24073280,
FT ECO:0007744|PDB:4ILW"
FT SITE 40
FT /note="Involved in metalloproteinase-binding"
FT /evidence="ECO:0000269|PubMed:24073280,
FT ECO:0007744|PDB:4ILW"
FT SITE 61
FT /note="Involved in metalloproteinase-binding"
FT /evidence="ECO:0000269|PubMed:24073280,
FT ECO:0007744|PDB:4ILW"
FT SITE 67
FT /note="Involved in metalloproteinase-binding"
FT /evidence="ECO:0000269|PubMed:24073280,
FT ECO:0007744|PDB:4ILW"
FT DISULFID 27..98
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00295,
FT ECO:0000269|PubMed:12032297"
FT DISULFID 29..127
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00295,
FT ECO:0000269|PubMed:12032297"
FT DISULFID 39..152
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00295,
FT ECO:0000269|PubMed:12032297"
FT DISULFID 154..201
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00295,
FT ECO:0000269|PubMed:12032297"
FT DISULFID 159..164
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00295,
FT ECO:0000269|PubMed:12032297"
FT DISULFID 172..193
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00295,
FT ECO:0000269|PubMed:12032297"
FT CONFLICT 17..19
FT /note="LAT -> P (in Ref. 3; AAC50729)"
FT /evidence="ECO:0000305"
FT CONFLICT 44..50
FT /note="VIRAKAV -> GKESGDP (in Ref. 10)"
FT /evidence="ECO:0000305"
FT CONFLICT 78
FT /note="M -> K (in Ref. 6; AA sequence and 7; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 82
FT /note="P -> I (in Ref. 6; AA sequence and 7; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 96
FT /note="A -> V (in Ref. 5; CAA38400)"
FT /evidence="ECO:0000305"
FT CONFLICT 101
FT /note="S -> E (in Ref. 6; AA sequence and 7; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 118
FT /note="Missing (in Ref. 6; AA sequence and 7; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 122
FT /note="M -> R (in Ref. 6; AA sequence and 7; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 150
FT /note="M -> Q (in Ref. 6; AA sequence and 7; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 175
FT /note="M -> T (in Ref. 6; AA sequence and 7; AA sequence)"
FT /evidence="ECO:0000305"
FT HELIX 34..40
FT /evidence="ECO:0007829|PDB:1BR9"
FT STRAND 41..59
FT /evidence="ECO:0007829|PDB:1BR9"
FT STRAND 61..63
FT /evidence="ECO:0007829|PDB:4ILW"
FT STRAND 65..81
FT /evidence="ECO:0007829|PDB:1BR9"
FT STRAND 88..91
FT /evidence="ECO:0007829|PDB:1BR9"
FT HELIX 95..97
FT /evidence="ECO:0007829|PDB:1BR9"
FT TURN 104..107
FT /evidence="ECO:0007829|PDB:4ILW"
FT STRAND 109..118
FT /evidence="ECO:0007829|PDB:1BR9"
FT STRAND 121..123
FT /evidence="ECO:0007829|PDB:1BR9"
FT STRAND 130..132
FT /evidence="ECO:0007829|PDB:1BR9"
FT HELIX 133..135
FT /evidence="ECO:0007829|PDB:1BR9"
FT HELIX 138..143
FT /evidence="ECO:0007829|PDB:1BR9"
FT TURN 144..148
FT /evidence="ECO:0007829|PDB:1BR9"
FT HELIX 149..151
FT /evidence="ECO:0007829|PDB:1BR9"
FT STRAND 154..158
FT /evidence="ECO:0007829|PDB:1BR9"
FT STRAND 161..163
FT /evidence="ECO:0007829|PDB:1BR9"
FT STRAND 171..174
FT /evidence="ECO:0007829|PDB:1BR9"
FT HELIX 176..180
FT /evidence="ECO:0007829|PDB:1BR9"
FT STRAND 181..185
FT /evidence="ECO:0007829|PDB:1GXD"
FT HELIX 186..190
FT /evidence="ECO:0007829|PDB:1BR9"
FT STRAND 192..195
FT /evidence="ECO:0007829|PDB:1BR9"
FT STRAND 197..199
FT /evidence="ECO:0007829|PDB:4ILW"
FT STRAND 201..204
FT /evidence="ECO:0007829|PDB:1BR9"
SQ SEQUENCE 220 AA; 24399 MW; 603E5B1C9F94735D CRC64;
MGAAARTLRL ALGLLLLATL LRPADACSCS PVHPQQAFCN ADVVIRAKAV SEKEVDSGND
IYGNPIKRIQ YEIKQIKMFK GPEKDIEFIY TAPSSAVCGV SLDVGGKKEY LIAGKAEGDG
KMHITLCDFI VPWDTLSTTQ KKSLNHRYQM GCECKITRCP MIPCYISSPD ECLWMDWVTE
KNINGHQAKF FACIKRSDGS CAWYRGAAPP KQEFLDIEDP
