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 27-NOV-2024, entry version 225. 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; P22830: FECH; NbExp=2; IntAct=EBI-1033507, EBI-1390356; CC P16035; P50281: MMP14; NbExp=4; IntAct=EBI-1033507, EBI-992788; CC P16035; P08253: MMP2; NbExp=3; 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="https://atlasgeneticsoncology.org/gene/42572/TIMP2"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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; 41. DR IntAct; P16035; 15. DR MINT; P16035; -. DR STRING; 9606.ENSP00000262768; -. DR MEROPS; I35.002; -. DR iPTMnet; P16035; -. DR PhosphoSitePlus; P16035; -. DR SwissPalm; P16035; -. DR BioMuta; TIMP2; -. DR DMDM; 135854; -. DR jPOST; P16035; -. DR MassIVE; P16035; -. DR PaxDb; 9606-ENSP00000262768; -. DR PeptideAtlas; P16035; -. DR ProteomicsDB; 53263; -. DR Pumba; P16035; -. DR TopDownProteomics; P16035; -. DR Antibodypedia; 4126; 1242 antibodies from 44 providers. DR DNASU; 7077; -. DR Ensembl; ENST00000262768.11; ENSP00000262768.6; ENSG00000035862.13. 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 AGR; HGNC:11821; -. 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; SAQDECL; -. DR OrthoDB; 5403389at2759; -. 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 Reactome; R-HSA-9839383; TGFBR3 PTM regulation. DR SignaLink; P16035; -. DR SIGNOR; P16035; -. DR BioGRID-ORCS; 7077; 20 hits in 1153 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 199 other cell types or tissues. DR ExpressionAtlas; P16035; baseline and differential. 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:0140678; F:molecular function inhibitor activity; IMP:DisProt. 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: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 CDD; cd03585; NTR_TIMP; 1. DR FunFam; 2.40.50.120:FF:000007; Metalloproteinase inhibitor 2; 1. DR FunFam; 3.90.370.10:FF:000001; Metalloproteinase inhibitor 3; 1. DR Gene3D; 2.40.50.120; -; 1. DR Gene3D; 3.90.370.10; Tissue inhibitor of metalloproteinase-1. Chain B, domain 1; 1. DR InterPro; IPR001134; Netrin_domain. DR InterPro; IPR001820; TIMP. DR InterPro; IPR008993; TIMP-like_OB-fold. DR InterPro; IPR027465; TIMP_C. DR InterPro; IPR030490; TIMP_CS. DR PANTHER; PTHR11844; METALLOPROTEASE INHIBITOR; 1. DR PANTHER; PTHR11844:SF24; METALLOPROTEINASE INHIBITOR 2; 1. DR Pfam; PF00965; TIMP; 1. DR SMART; SM00206; NTR; 1. DR SUPFAM; SSF50242; TIMP-like; 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 Proteomics identification; 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 //