Metalloproteinase inhibitor 1

NameMetalloproteinase inhibitor 1
Synonyms
  • CLGI
  • Collagenase inhibitor
  • EPA
  • Erythroid-potentiating activity
  • Fibroblast collagenase inhibitor
  • TIMP
  • TIMP-1
  • Tissue inhibitor of metalloproteinases 1
Gene NameTIMP1
OrganismHuman
Amino acid sequence
>lcl|BSEQ0019751|Metalloproteinase inhibitor 1
MAPFEPLASGILLLLWLIAPSRACTCVPPHPQTAFCNSDLVIRAKFVGTPEVNQTTLYQR
YEIKMTKMYKGFQALGDAADIRFVYTPAMESVCGYFHRSHNRSEEFLIAGKLQDGLLHIT
TCSFVAPWNSLSLAQRRGFTKTYTVGCEECTVFPCLSIPCKLQSGTHCLWTDQLLQGSEK
GFQSRHLACLPREPGLCTWQSLRSQIA
Number of residues207
Molecular Weight23170.64
Theoretical pINot Available
GO Classification
Functions
  • metal ion binding
  • metalloendopeptidase inhibitor activity
  • protease binding
  • cytokine activity
Processes
  • response to hormone
  • platelet activation
  • cartilage development
  • negative regulation of membrane protein ectodomain proteolysis
  • regulation of integrin-mediated signaling pathway
  • negative regulation of metalloenzyme activity
  • extracellular matrix disassembly
  • negative regulation of trophoblast cell migration
  • extracellular matrix organization
  • response to peptide hormone
  • negative regulation of apoptotic process
  • platelet degranulation
  • positive regulation of cell proliferation
  • negative regulation of endopeptidase activity
  • blood coagulation
  • aging
  • response to cytokine
Components
  • proteinaceous extracellular matrix
  • basement membrane
  • extracellular exosome
  • platelet alpha granule lumen
  • extracellular region
  • extracellular space
General FunctionProtease binding
Specific FunctionMetalloproteinase inhibitor that functions by forming one to one complexes with target metalloproteinases, such as collagenases, and irreversibly inactivates them by binding to their catalytic zinc cofactor. Acts on MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP10, MMP11, MMP12, MMP13 and MMP16. Does not act on MMP14. Also functions as a growth factor that regulates cell differentiation, migration and cell death and activates cellular signaling cascades via CD63 and ITGB1. Plays a role in integrin signaling. Mediates erythropoiesis in vitro; but, unlike IL3, it is species-specific, stimulating the growth and differentiation of only human and murine erythroid progenitors.
Pfam Domain Function
Transmembrane RegionsNot Available
GenBank Protein IDNot Available
UniProtKB IDP01033
UniProtKB Entry NameTIMP1_HUMAN
Cellular LocationSecreted
Gene sequence
>lcl|BSEQ0019752|Metalloproteinase inhibitor 1 (TIMP1)
ATGGCCCCCTTTGAGCCCCTGGCTTCTGGCATCCTGTTGTTGCTGTGGCTGATAGCCCCC
AGCAGGGCCTGCACCTGTGTCCCACCCCACCCACAGACGGCCTTCTGCAATTCCGACCTC
GTCATCAGGGCCAAGTTCGTGGGGACACCAGAAGTCAACCAGACCACCTTATACCAGCGT
TATGAGATCAAGATGACCAAGATGTATAAAGGGTTCCAAGCCTTAGGGGATGCCGCTGAC
ATCCGGTTCGTCTACACCCCCGCCATGGAGAGTGTCTGCGGATACTTCCACAGGTCCCAC
AACCGCAGCGAGGAGTTTCTCATTGCTGGAAAACTGCAGGATGGACTCTTGCACATCACT
ACCTGCAGTTTTGTGGCTCCCTGGAACAGCCTGAGCTTAGCTCAGCGCCGGGGCTTCACC
AAGACCTACACTGTTGGCTGTGAGGAATGCACAGTGTTTCCCTGTTTATCCATCCCCTGC
AAACTGCAGAGTGGCACTCATTGCTTGTGGACGGACCAGCTCCTCCAAGGCTCTGAAAAG
GGCTTCCAGTCCCGTCACCTTGCCTGCCTGCCTCGGGAGCCAGGGCTGTGCACCTGGCAG
TCCCTGCGGTCCCAGATAGCCTGA
GenBank Gene IDNot Available
GeneCard IDNot Available
GenAtlas IDNot Available
HGNC IDHGNC:11820
Chromosome LocationX
LocusNot Available
References
  1. Docherty AJ, Lyons A, Smith BJ, Wright EM, Stephens PE, Harris TJ, Murphy G, Reynolds JJ: Sequence of human tissue inhibitor of metalloproteinases and its identity to erythroid-potentiating activity. Nature. 1985 Nov 7-13;318(6041):66-9. 3903517
  2. Gasson JC, Golde DW, Kaufman SE, Westbrook CA, Hewick RM, Kaufman RJ, Wong GG, Temple PA, Leary AC, Brown EL, et al.: Molecular characterization and expression of the gene encoding human erythroid-potentiating activity. Nature. 1985 Jun 27-Jul 3;315(6022):768-71. 3839290
  3. Carmichael DF, Sommer A, Thompson RC, Anderson DC, Smith CG, Welgus HG, Stricklin GP: Primary structure and cDNA cloning of human fibroblast collagenase inhibitor. Proc Natl Acad Sci U S A. 1986 Apr;83(8):2407-11. 3010309
  4. Rapp G, Freudenstein J, Klaudiny J, Mucha J, Wempe F, Zimmer M, Scheit KH: Characterization of three abundant mRNAs from human ovarian granulosa cells. DNA Cell Biol. 1990 Sep;9(7):479-85. 2171551
  5. Opbroek A, Kenney MC, Brown D: Characterization of a human corneal metalloproteinase inhibitor (TIMP-1). Curr Eye Res. 1993 Oct;12(10):877-83. 7507419
  6. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. 15489334
  7. Hardcastle AJ, Thiselton DL, Nayudu M, Hampson RM, Bhattacharya SS: Genomic organization of the human TIMP-1 gene. Investigation of a causative role in the pathogenesis of X-linked retinitis pigmentosa 2. Invest Ophthalmol Vis Sci. 1997 Aug;38(9):1893-6. 9286280
  8. Osthues A, Knauper V, Oberhoff R, Reinke H, Tschesche H: Isolation and characterization of tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) from human rheumatoid synovial fluid. FEBS Lett. 1992 Jan 13;296(1):16-20. 1730286
  9. Van Ranst M, Norga K, Masure S, Proost P, Vandekerckhove F, Auwerx J, Van Damme J, Opdenakker G: The cytokine-protease connection: identification of a 96-kD THP-1 gelatinase and regulation by interleukin-1 and cytokine inducers. Cytokine. 1991 May;3(3):231-9. 1653055
  10. Zhang Z, Henzel WJ: Signal peptide prediction based on analysis of experimentally verified cleavage sites. Protein Sci. 2004 Oct;13(10):2819-24. Epub 2004 Aug 31. 15340161
  11. Williamson RA, Marston FA, Angal S, Koklitis P, Panico M, Morris HR, Carne AF, Smith BJ, Harris TJ, Freedman RB: Disulphide bond assignment in human tissue inhibitor of metalloproteinases (TIMP). Biochem J. 1990 Jun 1;268(2):267-74. 2163605
  12. O'Shea M, Willenbrock F, Williamson RA, Cockett MI, Freedman RB, Reynolds JJ, Docherty AJ, Murphy G: Site-directed mutations that alter the inhibitory activity of the tissue inhibitor of metalloproteinases-1: importance of the N-terminal region between cysteine 3 and cysteine 13. Biochemistry. 1992 Oct 27;31(42):10146-52. 1420137
  13. Chesler L, Golde DW, Bersch N, Johnson MD: Metalloproteinase inhibition and erythroid potentiation are independent activities of tissue inhibitor of metalloproteinases-1. Blood. 1995 Dec 15;86(12):4506-15. 8541540
  14. Knauper V, Lopez-Otin C, Smith B, Knight G, Murphy G: Biochemical characterization of human collagenase-3. J Biol Chem. 1996 Jan 19;271(3):1544-50. 8576151
  15. Knauper V, Cowell S, Smith B, Lopez-Otin C, O'Shea M, Morris H, Zardi L, Murphy G: The role of the C-terminal domain of human collagenase-3 (MMP-13) in the activation of procollagenase-3, substrate specificity, and tissue inhibitor of metalloproteinase interaction. J Biol Chem. 1997 Mar 21;272(12):7608-16. 9065415
  16. Liu T, Qian WJ, Gritsenko MA, Camp DG 2nd, Monroe ME, Moore RJ, Smith RD: Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry. J Proteome Res. 2005 Nov-Dec;4(6):2070-80. 16335952
  17. Jung KK, Liu XW, Chirco R, Fridman R, Kim HR: Identification of CD63 as a tissue inhibitor of metalloproteinase-1 interacting cell surface protein. EMBO J. 2006 Sep 6;25(17):3934-42. Epub 2006 Aug 17. 16917503
  18. Ramachandran P, Boontheung P, Xie Y, Sondej M, Wong DT, Loo JA: Identification of N-linked glycoproteins in human saliva by glycoprotein capture and mass spectrometry. J Proteome Res. 2006 Jun;5(6):1493-503. 16740002
  19. Lewandrowski U, Moebius J, Walter U, Sickmann A: Elucidation of N-glycosylation sites on human platelet proteins: a glycoproteomic approach. Mol Cell Proteomics. 2006 Feb;5(2):226-33. Epub 2005 Oct 31. 16263699
  20. Jia W, Lu Z, Fu Y, Wang HP, Wang LH, Chi H, Yuan ZF, Zheng ZB, Song LN, Han HH, Liang YM, Wang JL, Cai Y, Zhang YK, Deng YL, Ying WT, He SM, Qian XH: A strategy for precise and large scale identification of core fucosylated glycoproteins. Mol Cell Proteomics. 2009 May;8(5):913-23. doi: 10.1074/mcp.M800504-MCP200. Epub 2009 Jan 12. 19139490
  21. Burkard TR, Planyavsky M, Kaupe I, Breitwieser FP, Burckstummer T, Bennett KL, Superti-Furga G, Colinge J: Initial characterization of the human central proteome. BMC Syst Biol. 2011 Jan 26;5:17. doi: 10.1186/1752-0509-5-17. 21269460
  22. Rosenow A, Noben JP, Jocken J, Kallendrusch S, Fischer-Posovszky P, Mariman EC, Renes J: Resveratrol-induced changes of the human adipocyte secretion profile. J Proteome Res. 2012 Sep 7;11(9):4733-43. doi: 10.1021/pr300539b. Epub 2012 Aug 27. 22905912
  23. Toricelli M, Melo FH, Peres GB, Silva DC, Jasiulionis MG: Timp1 interacts with beta-1 integrin and CD63 along melanoma genesis and confers anoikis resistance by activating PI3-K signaling pathway independently of Akt phosphorylation. Mol Cancer. 2013 Mar 25;12:22. doi: 10.1186/1476-4598-12-22. 23522389
  24. Lee SY, Kim JM, Cho SY, Kim HS, Shin HS, Jeon JY, Kausar R, Jeong SY, Lee YS, Lee MA: TIMP-1 modulates chemotaxis of human neural stem cells through CD63 and integrin signalling. Biochem J. 2014 May 1;459(3):565-76. doi: 10.1042/BJ20131119. 24635319
  25. Ries C: Cytokine functions of TIMP-1. Cell Mol Life Sci. 2014 Feb;71(4):659-72. doi: 10.1007/s00018-013-1457-3. Epub 2013 Aug 28. 23982756
  26. Tagliabracci VS, Wiley SE, Guo X, Kinch LN, Durrant E, Wen J, Xiao J, Cui J, Nguyen KB, Engel JL, Coon JJ, Grishin N, Pinna LA, Pagliarini DJ, Dixon JE: A Single Kinase Generates the Majority of the Secreted Phosphoproteome. Cell. 2015 Jun 18;161(7):1619-32. doi: 10.1016/j.cell.2015.05.028. 26091039
  27. Gomis-Ruth FX, Maskos K, Betz M, Bergner A, Huber R, Suzuki K, Yoshida N, Nagase H, Brew K, Bourenkov GP, Bartunik H, Bode W: Mechanism of inhibition of the human matrix metalloproteinase stromelysin-1 by TIMP-1. Nature. 1997 Sep 4;389(6646):77-81. 9288970
  28. Wu B, Arumugam S, Gao G, Lee GI, Semenchenko V, Huang W, Brew K, Van Doren SR: NMR structure of tissue inhibitor of metalloproteinases-1 implicates localized induced fit in recognition of matrix metalloproteinases. J Mol Biol. 2000 Jan 14;295(2):257-68. 10623524
  29. Arumugam S, Van Doren SR: Global orientation of bound MMP-3 and N-TIMP-1 in solution via residual dipolar couplings. Biochemistry. 2003 Jul 8;42(26):7950-8. 12834347
  30. Iyer S, Wei S, Brew K, Acharya KR: Crystal structure of the catalytic domain of matrix metalloproteinase-1 in complex with the inhibitory domain of tissue inhibitor of metalloproteinase-1. J Biol Chem. 2007 Jan 5;282(1):364-71. Epub 2006 Oct 18. 17050530
  31. Grossman M, Tworowski D, Dym O, Lee MH, Levy Y, Murphy G, Sagi I: The intrinsic protein flexibility of endogenous protease inhibitor TIMP-1 controls its binding interface and affects its function. Biochemistry. 2010 Jul 27;49(29):6184-92. doi: 10.1021/bi902141x. 20545310
  32. Batra J, Robinson J, Soares AS, Fields AP, Radisky DC, Radisky ES: Matrix metalloproteinase-10 (MMP-10) interaction with tissue inhibitors of metalloproteinases TIMP-1 and TIMP-2: binding studies and crystal structure. J Biol Chem. 2012 May 4;287(19):15935-46. doi: 10.1074/jbc.M112.341156. Epub 2012 Mar 16. 22427646