Thrombomodulin

Details

Name
Thrombomodulin
Synonyms
  • Fetomodulin
  • THRM
  • TM
Gene Name
THBD
Organism
Humans
Amino acid sequence
>lcl|BSEQ0016328|Thrombomodulin
MLGVLVLGALALAGLGFPAPAEPQPGGSQCVEHDCFALYPGPATFLNASQICDGLRGHLM
TVRSSVAADVISLLLNGDGGVGRRRLWIGLQLPPGCGDPKRLGPLRGFQWVTGDNNTSYS
RWARLDLNGAPLCGPLCVAVSAAEATVPSEPIWEEQQCEVKADGFLCEFHFPATCRPLAV
EPGAAAAAVSITYGTPFAARGADFQALPVGSSAAVAPLGLQLMCTAPPGAVQGHWAREAP
GAWDCSVENGGCEHACNAIPGAPRCQCPAGAALQADGRSCTASATQSCNDLCEHFCVPNP
DQPGSYSCMCETGYRLAADQHRCEDVDDCILEPSPCPQRCVNTQGGFECHCYPNYDLVDG
ECVEPVDPCFRANCEYQCQPLNQTSYLCVCAEGFAPIPHEPHRCQMFCNQTACPADCDPN
TQASCECPEGYILDDGFICTDIDECENGGFCSGVCHNLPGTFECICGPDSALARHIGTDC
DSGKVDGGDSGSGEPPPSPTPGSTLTPPAVGLVHSGLLIGISIASLCLVVALLALLCHLR
KKQGAARAKMEYKCAAPSKEVVLQHVRTERTPQRL
Number of residues
575
Molecular Weight
60328.72
Theoretical pI
4.54
GO Classification
Functions
calcium ion binding / receptor activity / transmembrane signaling receptor activity
Processes
blood coagulation / female pregnancy / leukocyte migration / negative regulation of blood coagulation / negative regulation of fibrinolysis / negative regulation of platelet activation / response to cAMP / response to lipopolysaccharide / response to X-ray
Components
cell surface / extracellular space / integral component of plasma membrane / plasma membrane
General Function
Transmembrane signaling receptor activity
Specific Function
Thrombomodulin is a specific endothelial cell receptor that forms a 1:1 stoichiometric complex with thrombin. This complex is responsible for the conversion of protein C to the activated protein C (protein Ca). Once evolved, protein Ca scissions the activated cofactors of the coagulation mechanism, factor Va and factor VIIIa, and thereby reduces the amount of thrombin generated.
Pfam Domain Function
Transmembrane Regions
516-539
Cellular Location
Membrane
Gene sequence
>lcl|BSEQ0016329|Thrombomodulin (THBD)
ATGCTTGGGGTCCTGGTCCTTGGCGCGCTGGCCCTGGCCGGCCTGGGGTTCCCCGCACCC
GCAGAGCCGCAGCCGGGTGGCAGCCAGTGCGTCGAGCACGACTGCTTCGCGCTCTACCCG
GGCCCCGCGACCTTCCTCAATGCCAGTCAGATCTGCGACGGACTGCGGGGCCACCTAATG
ACAGTGCGCTCCTCGGTGGCTGCCGATGTCATTTCCTTGCTACTGAACGGCGACGGCGGC
GTTGGCCGCCGGCGCCTCTGGATCGGCCTGCAGCTGCCACCCGGCTGCGGCGACCCCAAG
CGCCTCGGGCCCCTGCGCGGCTTCCAGTGGGTTACGGGAGACAACAACACCAGCTATAGC
AGGTGGGCACGGCTCGACCTCAATGGGGCTCCCCTCTGCGGCCCGTTGTGCGTCGCTGTC
TCCGCTGCTGAGGCCACTGTGCCCAGCGAGCCGATCTGGGAGGAGCAGCAGTGCGAAGTG
AAGGCCGATGGCTTCCTCTGCGAGTTCCACTTCCCAGCCACCTGCAGGCCACTGGCTGTG
GAGCCCGGCGCCGCGGCTGCCGCCGTCTCGATCACCTACGGCACCCCGTTCGCGGCCCGC
GGAGCGGACTTCCAGGCGCTGCCGGTGGGCAGCTCCGCCGCGGTGGCTCCCCTCGGCTTA
CAGCTAATGTGCACCGCGCCGCCCGGAGCGGTCCAGGGGCACTGGGCCAGGGAGGCGCCG
GGCGCTTGGGACTGCAGCGTGGAGAACGGCGGCTGCGAGCACGCGTGCAATGCGATCCCT
GGGGCTCCCCGCTGCCAGTGCCCAGCCGGCGCCGCCCTGCAGGCAGACGGGCGCTCCTGC
ACCGCATCCGCGACGCAGTCCTGCAACGACCTCTGCGAGCACTTCTGCGTTCCCAACCCC
GACCAGCCGGGCTCCTACTCGTGCATGTGCGAGACCGGCTACCGGCTGGCGGCCGACCAA
CACCGGTGCGAGGACGTGGATGACTGCATACTGGAGCCCAGTCCGTGTCCGCAGCGCTGT
GTCAACACACAGGGTGGCTTCGAGTGCCACTGCTACCCTAACTACGACCTGGTGGACGGC
GAGTGTGTGGAGCCCGTGGACCCGTGCTTCAGAGCCAACTGCGAGTACCAGTGCCAGCCC
CTGAACCAAACTAGCTACCTCTGCGTCTGCGCCGAGGGCTTCGCGCCCATTCCCCACGAG
CCGCACAGGTGCCAGATGTTTTGCAACCAGACTGCCTGTCCAGCCGACTGCGACCCCAAC
ACCCAGGCTAGCTGTGAGTGCCCTGAAGGCTACATCCTGGACGACGGTTTCATCTGCACG
GACATCGACGAGTGCGAAAACGGCGGCTTCTGCTCCGGGGTGTGCCACAACCTCCCCGGT
ACCTTCGAGTGCATCTGCGGGCCCGACTCGGCCCTTGCCCGCCACATTGGCACCGACTGT
GACTCCGGCAAGGTGGACGGTGGCGACAGCGGCTCTGGCGAGCCCCCGCCCAGCCCGACG
CCCGGCTCCACCTTGACTCCTCCGGCCGTGGGGCTCGTGCATTCGGGCTTGCTCATAGGC
ATCTCCATCGCGAGCCTGTGCCTGGTGGTGGCGCTTTTGGCGCTCCTCTGCCACCTGCGC
AAGAAGCAGGGCGCCGCCAGGGCCAAGATGGAGTACAAGTGCGCGGCCCCTTCCAAGGAG
GTAGTGCTGCAGCACGTGCGGACCGAGCGGACGCCGCAGAGACTCTGA
Chromosome Location
20
Locus
20p12-cen
External Identifiers
ResourceLink
UniProtKB IDP07204
UniProtKB Entry NameTRBM_HUMAN
GenBank Protein ID736251
GenBank Gene IDX05495
GenAtlas IDTHBD
HGNC IDHGNC:11784
General References
  1. Suzuki K, Kusumoto H, Deyashiki Y, Nishioka J, Maruyama I, Zushi M, Kawahara S, Honda G, Yamamoto S, Horiguchi S: Structure and expression of human thrombomodulin, a thrombin receptor on endothelium acting as a cofactor for protein C activation. EMBO J. 1987 Jul;6(7):1891-7. [PubMed:2820710]
  2. Wen DZ, Dittman WA, Ye RD, Deaven LL, Majerus PW, Sadler JE: Human thrombomodulin: complete cDNA sequence and chromosome localization of the gene. Biochemistry. 1987 Jul 14;26(14):4350-7. [PubMed:2822087]
  3. Jackman RW, Beeler DL, Fritze L, Soff G, Rosenberg RD: Human thrombomodulin gene is intron depleted: nucleic acid sequences of the cDNA and gene predict protein structure and suggest sites of regulatory control. Proc Natl Acad Sci U S A. 1987 Sep;84(18):6425-9. [PubMed:2819876]
  4. Shirai T, Shiojiri S, Ito H, Yamamoto S, Kusumoto H, Deyashiki Y, Maruyama I, Suzuki K: Gene structure of human thrombomodulin, a cofactor for thrombin-catalyzed activation of protein C. J Biochem. 1988 Feb;103(2):281-5. [PubMed:2836377]
  5. Deloukas P, Matthews LH, Ashurst J, Burton J, Gilbert JG, Jones M, Stavrides G, Almeida JP, Babbage AK, Bagguley CL, Bailey J, Barlow KF, Bates KN, Beard LM, Beare DM, Beasley OP, Bird CP, Blakey SE, Bridgeman AM, Brown AJ, Buck D, Burrill W, Butler AP, Carder C, Carter NP, Chapman JC, Clamp M, Clark G, Clark LN, Clark SY, Clee CM, Clegg S, Cobley VE, Collier RE, Connor R, Corby NR, Coulson A, Coville GJ, Deadman R, Dhami P, Dunn M, Ellington AG, Frankland JA, Fraser A, French L, Garner P, Grafham DV, Griffiths C, Griffiths MN, Gwilliam R, Hall RE, Hammond S, Harley JL, Heath PD, Ho S, Holden JL, Howden PJ, Huckle E, Hunt AR, Hunt SE, Jekosch K, Johnson CM, Johnson D, Kay MP, Kimberley AM, King A, Knights A, Laird GK, Lawlor S, Lehvaslaiho MH, Leversha M, Lloyd C, Lloyd DM, Lovell JD, Marsh VL, Martin SL, McConnachie LJ, McLay K, McMurray AA, Milne S, Mistry D, Moore MJ, Mullikin JC, Nickerson T, Oliver K, Parker A, Patel R, Pearce TA, Peck AI, Phillimore BJ, Prathalingam SR, Plumb RW, Ramsay H, Rice CM, Ross MT, Scott CE, Sehra HK, Shownkeen R, Sims S, Skuce CD, Smith ML, Soderlund C, Steward CA, Sulston JE, Swann M, Sycamore N, Taylor R, Tee L, Thomas DW, Thorpe A, Tracey A, Tromans AC, Vaudin M, Wall M, Wallis JM, Whitehead SL, Whittaker P, Willey DL, Williams L, Williams SA, Wilming L, Wray PW, Hubbard T, Durbin RM, Bentley DR, Beck S, Rogers J: The DNA sequence and comparative analysis of human chromosome 20. Nature. 2001 Dec 20-27;414(6866):865-71. [PubMed:11780052]
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  7. Gerlitz B, Hassell T, Vlahos CJ, Parkinson JF, Bang NU, Grinnell BW: Identification of the predominant glycosaminoglycan-attachment site in soluble recombinant human thrombomodulin: potential regulation of functionality by glycosyltransferase competition for serine474. Biochem J. 1993 Oct 1;295 ( Pt 1):131-40. [PubMed:8216207]
  8. Yamamoto S, Mizoguchi T, Tamaki T, Ohkuchi M, Kimura S, Aoki N: Urinary thrombomodulin, its isolation and characterization. J Biochem. 1993 Apr;113(4):433-40. [PubMed:8390446]
  9. Adler M, Seto MH, Nitecki DE, Lin JH, Light DR, Morser J: The structure of a 19-residue fragment from the C-loop of the fourth epidermal growth factor-like domain of thrombomodulin. J Biol Chem. 1995 Oct 6;270(40):23366-72. [PubMed:7559494]
  10. Meininger DP, Hunter MJ, Komives EA: Synthesis, activity, and preliminary structure of the fourth EGF-like domain of thrombomodulin. Protein Sci. 1995 Sep;4(9):1683-95. [PubMed:8528067]
  11. Srinivasan J, Hu S, Hrabal R, Zhu Y, Komives EA, Ni F: Thrombin-bound structure of an EGF subdomain from human thrombomodulin determined by transferred nuclear Overhauser effects. Biochemistry. 1994 Nov 22;33(46):13553-60. [PubMed:7947766]
  12. Hrabal R, Komives EA, Ni F: Structural resiliency of an EGF-like subdomain bound to its target protein, thrombin. Protein Sci. 1996 Feb;5(2):195-203. [PubMed:8745396]
  13. Sampoli Benitez BA, Hunter MJ, Meininger DP, Komives EA: Structure of the fifth EGF-like domain of thrombomodulin: An EGF-like domain with a novel disulfide-bonding pattern. J Mol Biol. 1997 Nov 7;273(4):913-26. [PubMed:9367781]
  14. Ohlin AK, Marlar RA: The first mutation identified in the thrombomodulin gene in a 45-year-old man presenting with thromboembolic disease. Blood. 1995 Jan 15;85(2):330-6. [PubMed:7811989]
  15. Ohlin AK, Norlund L, Marlar RA: Thrombomodulin gene variations and thromboembolic disease. Thromb Haemost. 1997 Jul;78(1):396-400. [PubMed:9198186]
  16. Norlund L, Holm J, Zoller B, Ohlin AK: A common thrombomodulin amino acid dimorphism is associated with myocardial infarction. Thromb Haemost. 1997 Feb;77(2):248-51. [PubMed:9157575]
  17. Doggen CJ, Kunz G, Rosendaal FR, Lane DA, Vos HL, Stubbs PJ, Manger Cats V, Ireland H: A mutation in the thrombomodulin gene, 127G to A coding for Ala25Thr, and the risk of myocardial infarction in men. Thromb Haemost. 1998 Nov;80(5):743-8. [PubMed:9843165]
  18. Wu KK, Aleksic N, Ahn C, Boerwinkle E, Folsom AR, Juneja H: Thrombomodulin Ala455Val polymorphism and risk of coronary heart disease. Circulation. 2001 Mar 13;103(10):1386-9. [PubMed:11245641]
  19. Faioni EM, Franchi F, Castaman G, Biguzzi E, Rodeghiero F: Mutations in the thrombomodulin gene are rare in patients with severe thrombophilia. Br J Haematol. 2002 Aug;118(2):595-9. [PubMed:12139752]
  20. Delvaeye M, Noris M, De Vriese A, Esmon CT, Esmon NL, Ferrell G, Del-Favero J, Plaisance S, Claes B, Lambrechts D, Zoja C, Remuzzi G, Conway EM: Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl J Med. 2009 Jul 23;361(4):345-57. doi: 10.1056/NEJMoa0810739. [PubMed:19625716]
  21. Maga TK, Nishimura CJ, Weaver AE, Frees KL, Smith RJ: Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome. Hum Mutat. 2010 Jun;31(6):E1445-60. doi: 10.1002/humu.21256. [PubMed:20513133]

Drug Relations

Drug Relations
DrugBank IDNameDrug groupPharmacological action?ActionsDetails
DB00055Drotrecogin alfaapproved, investigational, withdrawnunknownDetails
DB01050IbuprofenapprovedunknowninducerDetails
DB09213Dexibuprofenapproved, investigationalunknownmodulatorDetails