Collagenase 3

NameCollagenase 3
Synonyms
  • 3.4.24.-
  • Matrix metalloproteinase-13
  • MMP-13
Gene NameMMP13
OrganismHuman
Amino acid sequence
>lcl|BSEQ0010677|Collagenase 3
MHPGVLAAFLFLSWTHCRALPLPSGGDEDDLSEEDLQFAERYLRSYYHPTNLAGILKENA
ASSMTERLREMQSFFGLEVTGKLDDNTLDVMKKPRCGVPDVGEYNVFPRTLKWSKMNLTY
RIVNYTPDMTHSEVEKAFKKAFKVWSDVTPLNFTRLHDGIADIMISFGIKEHGDFYPFDG
PSGLLAHAFPPGPNYGGDAHFDDDETWTSSSKGYNLFLVAAHEFGHSLGLDHSKDPGALM
FPIYTYTGKSHFMLPDDDVQGIQSLYGPGDEDPNPKHPKTPDKCDPSLSLDAITSLRGET
MIFKDRFFWRLHPQQVDAELFLTKSFWPELPNRIDAAYEHPSHDLIFIFRGRKFWALNGY
DILEGYPKKISELGLPKEVKKISAAVHFEDTGKTLLFSGNQVWRYDDTNHIMDKDYPRLI
EEDFPGIGDKVDAVYEKNGYIYFFNGPIQFEYSIWSNRIVRVMPANSILWC
Number of residues471
Molecular Weight53819.32
Theoretical pI5.31
GO Classification
Functions
  • zinc ion binding
  • calcium ion binding
  • collagen binding
  • metalloendopeptidase activity
Processes
  • peptide catabolic process
  • collagen catabolic process
  • endochondral ossification
  • extracellular matrix disassembly
  • extracellular matrix organization
  • cellular protein metabolic process
  • response to hypoxia
  • response to estrogen
  • response to mechanical stimulus
  • bone mineralization
  • proteolysis
  • embryonic hindlimb morphogenesis
  • response to drug
  • bone morphogenesis
  • growth plate cartilage development
  • luteolysis
  • receptor internalization
Components
  • extracellular region
  • intercellular canaliculus
  • extracellular space
  • fibrillar collagen trimer
  • lysosome
  • Golgi apparatus
General FunctionZinc ion binding
Specific FunctionPlays a role in the degradation of extracellular matrix proteins including fibrillar collagen, fibronectin, TNC and ACAN. Cleaves triple helical collagens, including type I, type II and type III collagen, but has the highest activity with soluble type II collagen. Can also degrade collagen type IV, type XIV and type X. May also function by activating or degrading key regulatory proteins, such as TGFB1 and CTGF. Plays a role in wound healing, tissue remodeling, cartilage degradation, bone development, bone mineralization and ossification. Required for normal embryonic bone development and ossification. Plays a role in the healing of bone fractures via endochondral ossification. Plays a role in wound healing, probably by a mechanism that involves proteolytic activation of TGFB1 and degradation of CTGF. Plays a role in keratinocyte migration during wound healing. May play a role in cell migration and in tumor cell invasion.
Pfam Domain Function
Transmembrane RegionsNot Available
GenBank Protein ID516386
UniProtKB IDP45452
UniProtKB Entry NameMMP13_HUMAN
Cellular LocationSecreted
Gene sequence
>lcl|BSEQ0010678|Collagenase 3 (MMP13)
ATGCATCCAGGGGTCCTGGCTGCCTTCCTCTTCTTGAGCTGGACTCATTGTCGGGCCCTG
CCCCTTCCCAGTGGTGGTGATGAAGATGATTTGTCTGAGGAAGACCTCCAGTTTGCAGAG
CGCTACCTGAGATCATACTACCATCCTACAAATCTCGCGGGAATCCTGAAGGAGAATGCA
GCAAGCTCCATGACTGAGAGGCTCCGAGAAATGCAGTCTTTCTTCGGCTTAGAGGTGACT
GGCAAACTTGACGATAACACCTTAGATGTCATGAAAAAGCCAAGATGCGGGGTTCCTGAT
GTGGGTGAATACAATGTTTTCCCTCGAACTCTTAAATGGTCCAAAATGAATTTAACCTAC
AGAATTGTGAATTACACCCCTGATATGACTCATTCTGAAGTCGAAAAGGCATTCAAAAAA
GCCTTCAAAGTTTGGTCCGATGTAACTCCTCTGAATTTTACCAGACTTCACGATGGCATT
GCTGACATCATGATCTCTTTTGGAATTAAGGAGCATGGCGACTTCTACCCATTTGATGGG
CCCTCTGGCCTGCTGGCTCATGCTTTTCCTCCTGGGCCAAATTATGGAGGAGATGCCCAT
TTTGATGATGATGAAACCTGGACAAGTAGTTCCAAAGGCTACAACTTGTTTCTTGTTGCT
GCGCATGAGTTCGGCCACTCCTTAGGTCTTGACCACTCCAAGGACCCTGGAGCACTCATG
TTTCCTATCTACACCTACACCGGCAAAAGCCACTTTATGCTTCCTGATGACGATGTACAA
GGGATCCAGTCTCTCTATGGTCCAGGAGATGAAGACCCCAACCCTAAACATCCAAAAACG
CCAGACAAATGTGACCCTTCCTTATCCCTTGATGCCATTACCAGTCTCCGAGGAGAAACA
ATGATCTTTAAAGACAGATTCTTCTGGCGCCTGCATCCTCAGCAGGTTGATGCGGAGCTG
TTTTTAACGAAATCATTTTGGCCAGAACTTCCCAACCGTATTGATGCTGCATATGAGCAC
CCTTCTCATGACCTCATCTTCATCTTCAGAGGTAGAAAATTTTGGGCTCTTAATGGTTAT
GACATTCTGGAAGGTTATCCCAAAAAAATATCTGAACTGGGTCTTCCAAAAGAAGTTAAG
AAGATAAGTGCAGCTGTTCACTTTGAGGATACAGGCAAGACTCTCCTGTTCTCAGGAAAC
CAGGTCTGGAGATATGATGATACTAACCATATTATGGATAAAGACTATCCGAGACTAATA
GAAGAAGACTTCCCAGGAATTGGTGATAAAGTAGATGCTGTCTATGAGAAAAATGGTTAT
ATCTATTTTTTCAACGGACCCATACAGTTTGAATACAGCATCTGGAGTAACCGTATTGTT
CGCGTCATGCCAGCAAATTCCATTTTGTGGTGTTAA
GenBank Gene IDX75308
GeneCard IDNot Available
GenAtlas IDMMP13
HGNC IDHGNC:7159
Chromosome Location11
Locus11q22.3
References
  1. Freije JM, Diez-Itza I, Balbin M, Sanchez LM, Blasco R, Tolivia J, Lopez-Otin C: Molecular cloning and expression of collagenase-3, a novel human matrix metalloproteinase produced by breast carcinomas. J Biol Chem. 1994 Jun 17;269(24):16766-73. 8207000
  2. Willmroth F, Peter HH, Conca W: A matrix metalloproteinase gene expressed in human T lymphocytes is identical with collagenase 3 from breast carcinomas. Immunobiology. 1998 Feb;198(4):375-84. 9562863
  3. Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. Epub 2003 Dec 21. 14702039
  4. 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
  5. 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
  6. Knauper V, Will H, Lopez-Otin C, Smith B, Atkinson SJ, Stanton H, Hembry RM, Murphy G: Cellular mechanisms for human procollagenase-3 (MMP-13) activation. Evidence that MT1-MMP (MMP-14) and gelatinase a (MMP-2) are able to generate active enzyme. J Biol Chem. 1996 Jul 19;271(29):17124-31. 8663255
  7. Fosang AJ, Last K, Knauper V, Murphy G, Neame PJ: Degradation of cartilage aggrecan by collagenase-3 (MMP-13). FEBS Lett. 1996 Feb 12;380(1-2):17-20. 8603731
  8. Borden P, Solymar D, Sucharczuk A, Lindman B, Cannon P, Heller RA: Cytokine control of interstitial collagenase and collagenase-3 gene expression in human chondrocytes. J Biol Chem. 1996 Sep 20;271(38):23577-81. 8798568
  9. Johansson N, Saarialho-Kere U, Airola K, Herva R, Nissinen L, Westermarck J, Vuorio E, Heino J, Kahari VM: Collagenase-3 (MMP-13) is expressed by hypertrophic chondrocytes, periosteal cells, and osteoblasts during human fetal bone development. Dev Dyn. 1997 Mar;208(3):387-97. 9056642
  10. 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
  11. Bonafe L, Liang J, Gorna MW, Zhang Q, Ha-Vinh R, Campos-Xavier AB, Unger S, Beckmann JS, Le Bechec A, Stevenson B, Giedion A, Liu X, Superti-Furga G, Wang W, Spahr A, Superti-Furga A: MMP13 mutations are the cause of recessive metaphyseal dysplasia, Spahr type. Am J Med Genet A. 2014 May;164A(5):1175-9. doi: 10.1002/ajmg.a.36431. Epub 2014 Mar 19. 24648384
  12. Bordoli MR, Yum J, Breitkopf SB, Thon JN, Italiano JE Jr, Xiao J, Worby C, Wong SK, Lin G, Edenius M, Keller TL, Asara JM, Dixon JE, Yeo CY, Whitman M: A secreted tyrosine kinase acts in the extracellular environment. Cell. 2014 Aug 28;158(5):1033-44. doi: 10.1016/j.cell.2014.06.048. 25171405
  13. Li D, Weber DR, Deardorff MA, Hakonarson H, Levine MA: Exome sequencing reveals a nonsense mutation in MMP13 as a new cause of autosomal recessive metaphyseal anadysplasia. Eur J Hum Genet. 2015 Feb;23(2):264-6. doi: 10.1038/ejhg.2014.76. Epub 2014 Apr 30. 24781753
  14. Gomis-Ruth FX, Gohlke U, Betz M, Knauper V, Murphy G, Lopez-Otin C, Bode W: The helping hand of collagenase-3 (MMP-13): 2.7 A crystal structure of its C-terminal haemopexin-like domain. J Mol Biol. 1996 Dec 6;264(3):556-66. 8969305
  15. Lovejoy B, Welch AR, Carr S, Luong C, Broka C, Hendricks RT, Campbell JA, Walker KA, Martin R, Van Wart H, Browner MF: Crystal structures of MMP-1 and -13 reveal the structural basis for selectivity of collagenase inhibitors. Nat Struct Biol. 1999 Mar;6(3):217-21. 10074939
  16. Zhang X, Gonnella NC, Koehn J, Pathak N, Ganu V, Melton R, Parker D, Hu SI, Nam KY: Solution structure of the catalytic domain of human collagenase-3 (MMP-13) complexed to a potent non-peptidic sulfonamide inhibitor: binding comparison with stromelysin-1 and collagenase-1. J Mol Biol. 2000 Aug 11;301(2):513-24. 10926524
  17. Moy FJ, Chanda PK, Chen JM, Cosmi S, Edris W, Levin JI, Powers R: High-resolution solution structure of the catalytic fragment of human collagenase-3 (MMP-13) complexed with a hydroxamic acid inhibitor. J Mol Biol. 2000 Sep 22;302(3):671-89. 10986126
  18. Blagg JA, Noe MC, Wolf-Gouveia LA, Reiter LA, Laird ER, Chang SP, Danley DE, Downs JT, Elliott NC, Eskra JD, Griffiths RJ, Hardink JR, Haugeto AI, Jones CS, Liras JL, Lopresti-Morrow LL, Mitchell PG, Pandit J, Robinson RP, Subramanyam C, Vaughn-Bowser ML, Yocum SA: Potent pyrimidinetrione-based inhibitors of MMP-13 with enhanced selectivity over MMP-14. Bioorg Med Chem Lett. 2005 Apr 1;15(7):1807-10. 15780611
  19. Engel CK, Pirard B, Schimanski S, Kirsch R, Habermann J, Klingler O, Schlotte V, Weithmann KU, Wendt KU: Structural basis for the highly selective inhibition of MMP-13. Chem Biol. 2005 Feb;12(2):181-9. 15734645
  20. Johnson AR, Pavlovsky AG, Ortwine DF, Prior F, Man CF, Bornemeier DA, Banotai CA, Mueller WT, McConnell P, Yan C, Baragi V, Lesch C, Roark WH, Wilson M, Datta K, Guzman R, Han HK, Dyer RD: Discovery and characterization of a novel inhibitor of matrix metalloprotease-13 that reduces cartilage damage in vivo without joint fibroplasia side effects. J Biol Chem. 2007 Sep 21;282(38):27781-91. Epub 2007 Jul 10. 17623656
  21. Maskos K, Lang R, Tschesche H, Bode W: Flexibility and variability of TIMP binding: X-ray structure of the complex between collagenase-3/MMP-13 and TIMP-2. J Mol Biol. 2007 Mar 2;366(4):1222-31. Epub 2006 Dec 1. 17196980
  22. Monovich LG, Tommasi RA, Fujimoto RA, Blancuzzi V, Clark K, Cornell WD, Doti R, Doughty J, Fang J, Farley D, Fitt J, Ganu V, Goldberg R, Goldstein R, Lavoie S, Kulathila R, Macchia W, Parker DT, Melton R, O'Byrne E, Pastor G, Pellas T, Quadros E, Reel N, Roland DM, Sakane Y, Singh H, Skiles J, Somers J, Toscano K, Wigg A, Zhou S, Zhu L, Shieh WC, Xue S, McQuire LW: Discovery of potent, selective, and orally active carboxylic acid based inhibitors of matrix metalloproteinase-13. J Med Chem. 2009 Jun 11;52(11):3523-38. doi: 10.1021/jm801394m. 19422229
  23. Schnute ME, O'Brien PM, Nahra J, Morris M, Howard Roark W, Hanau CE, Ruminski PG, Scholten JA, Fletcher TR, Hamper BC, Carroll JN, Patt WC, Shieh HS, Collins B, Pavlovsky AG, Palmquist KE, Aston KW, Hitchcock J, Rogers MD, McDonald J, Johnson AR, Munie GE, Wittwer AJ, Man CF, Settle SL, Nemirovskiy O, Vickery LE, Agawal A, Dyer RD, Sunyer T: Discovery of (pyridin-4-yl)-2H-tetrazole as a novel scaffold to identify highly selective matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis. Bioorg Med Chem Lett. 2010 Jan 15;20(2):576-80. doi: 10.1016/j.bmcl.2009.11.081. Epub 2009 Nov 22. 20005097
  24. Becker DP, Barta TE, Bedell LJ, Boehm TL, Bond BR, Carroll J, Carron CP, Decrescenzo GA, Easton AM, Freskos JN, Funckes-Shippy CL, Heron M, Hockerman S, Howard CP, Kiefer JR, Li MH, Mathis KJ, McDonald JJ, Mehta PP, Munie GE, Sunyer T, Swearingen CA, Villamil CI, Welsch D, Williams JM, Yu Y, Yao J: Orally active MMP-1 sparing alpha-tetrahydropyranyl and alpha-piperidinyl sulfone matrix metalloproteinase (MMP) inhibitors with efficacy in cancer, arthritis, and cardiovascular disease. J Med Chem. 2010 Sep 23;53(18):6653-80. doi: 10.1021/jm100669j. 20726512
  25. Devel L, Beau F, Amoura M, Vera L, Cassar-Lajeunesse E, Garcia S, Czarny B, Stura EA, Dive V: Simple pseudo-dipeptides with a P2' glutamate: a novel inhibitor family of matrix metalloproteases and other metzincins. J Biol Chem. 2012 Aug 3;287(32):26647-56. doi: 10.1074/jbc.M112.380782. Epub 2012 Jun 11. 22689580
  26. De Savi C, Waterson D, Pape A, Lamont S, Hadley E, Mills M, Page KM, Bowyer J, Maciewicz RA: Hydantoin based inhibitors of MMP13--discovery of AZD6605. Bioorg Med Chem Lett. 2013 Aug 15;23(16):4705-12. doi: 10.1016/j.bmcl.2013.05.089. Epub 2013 Jun 10. 23810497
  27. Stura EA, Visse R, Cuniasse P, Dive V, Nagase H: Crystal structure of full-length human collagenase 3 (MMP-13) with peptides in the active site defines exosites in the catalytic domain. FASEB J. 2013 Nov;27(11):4395-405. doi: 10.1096/fj.13-233601. Epub 2013 Aug 2. 23913860
  28. Kennedy AM, Inada M, Krane SM, Christie PT, Harding B, Lopez-Otin C, Sanchez LM, Pannett AA, Dearlove A, Hartley C, Byrne MH, Reed AA, Nesbit MA, Whyte MP, Thakker RV: MMP13 mutation causes spondyloepimetaphyseal dysplasia, Missouri type (SEMD(MO). J Clin Invest. 2005 Oct;115(10):2832-42. 16167086
  29. Lausch E, Keppler R, Hilbert K, Cormier-Daire V, Nikkel S, Nishimura G, Unger S, Spranger J, Superti-Furga A, Zabel B: Mutations in MMP9 and MMP13 determine the mode of inheritance and the clinical spectrum of metaphyseal anadysplasia. Am J Hum Genet. 2009 Aug;85(2):168-78. doi: 10.1016/j.ajhg.2009.06.014. Epub 2009 Jul 16. 19615667