Thrombomodulin
(Redirected fromTHBD)
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | THBD,AHUS6, BDCA3, CD141, THPH12, THRM, TM, thrombomodulin, BDCA-3 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM:188040;MGI:98736;HomoloGene:308;GeneCards:THBD;OMA:THBD - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Thrombomodulin(TM),CD141 or BDCA-3 is anintegral membrane proteinexpressed on the surface ofendothelial cellsand serves as a cofactor forthrombin.It reducesblood coagulationby converting thrombin to an anticoagulantenzymefrom a procoagulant enzyme.[5]Thrombomodulin is also expressed on humanmesothelial cell,[6]monocyteand adendritic cellsubset.
Genetics and structure
[edit]In humans, thrombomodulin is encoded by theTHBDgene.[7]The protein has a molecular mass of 74kDa,and consists of a single chain with six tandemly repeatedEGF-like domains,aSerine/Threonine-rich spacer and atransmembranedomain.[8] It is a member of theC-type lectin domain(CTLD) group 14 family.[9]
Function
[edit]Thrombomodulin functions as acofactorin thethrombin-induced activation ofprotein Cin theanticoagulantpathway by forming a 1:1 stoichiometric complex with thrombin. This raises the speed of protein C activation thousandfold. Thrombomodulin-bound thrombin has procoagulant effect at the same time by inhibiting fibrinolysis by cleavingthrombin-activatable fibrinolysis inhibitor(TAFI, aka carboxypeptidase B2) into its active form.[citation needed]
Thrombomodulin is aglycoproteinon the surface of endothelial cells that, in addition to binding thrombin, regulatesC3binactivation by factor I. Mutations in the thrombomodulin gene (THBD) have also been reported to be associated withatypical hemolytic-uremic syndrome(aHUS).[10]
Theantigendescribed as BDCA-3[11]has turned out to be identical to thrombomodulin.[12]Thus, it was revealed that this molecule also occurs on a very rare (0.02%) subset of humandendritic cellscalled MDC2. Its function on these cells is unknown.[citation needed]
Interactions
[edit]Thrombomodulin has been shown tointeractwiththrombin.[13][14]
References
[edit]- ^abcGRCh38: Ensembl release 89: ENSG00000178726–Ensembl,May 2017
- ^abcGRCm38: Ensembl release 89: ENSMUSG00000074743–Ensembl,May 2017
- ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^IPR001491 ThrombomodulinAccessed January 19, 2012.
- ^Verhagen HJ, Heijnen-Snyder GJ, Pronk A, Vroom TM, van Vroonhoven TJ, Eikelboom BC, et al. (December 1996). "Thrombomodulin activity on mesothelial cells: perspectives for mesothelial cells as an alternative for endothelial cells for cell seeding on vascular grafts".British Journal of Haematology.95(3): 542–549.doi:10.1046/j.1365-2141.1996.d01-1935.x.PMID8943899.S2CID8417511.
- ^Wen DZ, Dittman WA, Ye RD, Deaven LL, Majerus PW, Sadler JE (July 1987). "Human thrombomodulin: complete cDNA sequence and chromosome localization of the gene".Biochemistry.26(14): 4350–4357.doi:10.1021/bi00388a025.PMID2822087.
- ^Sadler JE(July 1997). "Thrombomodulin structure and function".Thrombosis and Haemostasis.78(1): 392–395.doi:10.1055/s-0038-1657558.PMID9198185.S2CID32297505.
- ^Khan KA, McMurray JL, Mohammed F, Bicknell R (September 2019)."C-type lectin domain group 14 proteins in vascular biology, cancer and inflammation".The FEBS Journal.286(17): 3299–3332.doi:10.1111/febs.14985.PMC6852297.PMID31287944.
- ^Delvaeye M, Noris M, De Vriese A, Esmon CT, Esmon NL, Ferrell G, et al. (July 2009)."Thrombomodulin mutations in atypical hemolytic-uremic syndrome".The New England Journal of Medicine.361(4): 345–357.doi:10.1056/NEJMoa0810739.PMC3530919.PMID19625716.
- ^Dzionek A, Fuchs A, Schmidt P, Cremer S, Zysk M, Miltenyi S, et al. (December 2000)."BDCA-2, BDCA-3, and BDCA-4: three markers for distinct subsets of dendritic cells in human peripheral blood".Journal of Immunology.165(11): 6037–6046.doi:10.4049/jimmunol.165.11.6037.PMID11086035.
- ^Dzionek A, Inagaki Y, Okawa K, Nagafune J, Röck J, Sohma Y, et al. (December 2002). "Plasmacytoid dendritic cells: from specific surface markers to specific cellular functions".Human Immunology.63(12): 1133–1148.doi:10.1016/S0198-8859(02)00752-8.PMID12480257.
- ^Bajzar L, Morser J, Nesheim M (July 1996)."TAFI, or plasma procarboxypeptidase B, couples the coagulation and fibrinolytic cascades through the thrombin-thrombomodulin complex".The Journal of Biological Chemistry.271(28): 16603–16608.doi:10.1074/jbc.271.28.16603.PMID8663147.
- ^Jakubowski HV, Owen WG (July 1989)."Macromolecular specificity determinants on thrombin for fibrinogen and thrombomodulin".The Journal of Biological Chemistry.264(19): 11117–11121.doi:10.1016/S0021-9258(18)60437-5.PMID2544585.
Further reading
[edit]- Esmon CT (July 1995)."Thrombomodulin as a model of molecular mechanisms that modulate protease specificity and function at the vessel surface".FASEB Journal.9(10): 946–955.doi:10.1096/fasebj.9.10.7615164.PMID7615164.S2CID19565674.
- Ohlin AK, Norlund L, Marlar RA (July 1997). "Thrombomodulin gene variations and thromboembolic disease".Thrombosis and Haemostasis.78(1): 396–400.doi:10.1055/s-0038-1657559.PMID9198186.S2CID25122238.
- Van de Wouwer M, Collen D, Conway EM (August 2004). "Thrombomodulin-protein C-EPCR system: integrated to regulate coagulation and inflammation".Arteriosclerosis, Thrombosis, and Vascular Biology.24(8): 1374–1383.doi:10.1161/01.ATV.0000134298.25489.92.PMID15178554.
- Boffa MC, Jackman RW, Peyri N, Boffa JF, George B (1991). "Thrombomodulin in the central nervous system".Nouvelle Revue Française d'Hématologie.33(6): 423–429.PMID1667949.
- Jackman RW, Beeler DL, Fritze L, Soff G, Rosenberg RD (September 1987)."Human thrombomodulin gene is intron depleted: nucleic acid sequences of the cDNA and gene predict protein structure and suggest sites of regulatory control".Proceedings of the National Academy of Sciences of the United States of America.84(18): 6425–6429.Bibcode:1987PNAS...84.6425J.doi:10.1073/pnas.84.18.6425.PMC299089.PMID2819876.
- Suzuki K, Kusumoto H, Deyashiki Y, Nishioka J, Maruyama I, Zushi M, et al. (July 1987)."Structure and expression of human thrombomodulin, a thrombin receptor on endothelium acting as a cofactor for protein C activation".The EMBO Journal.6(7): 1891–1897.doi:10.1002/j.1460-2075.1987.tb02448.x.PMC553573.PMID2820710.
- Wen DZ, Dittman WA, Ye RD, Deaven LL, Majerus PW, Sadler JE (July 1987). "Human thrombomodulin: complete cDNA sequence and chromosome localization of the gene".Biochemistry.26(14): 4350–4357.doi:10.1021/bi00388a025.PMID2822087.
- Shirai T, Shiojiri S, Ito H, Yamamoto S, Kusumoto H, Deyashiki Y, et al. (February 1988). "Gene structure of human thrombomodulin, a cofactor for thrombin-catalyzed activation of protein C".Journal of Biochemistry.103(2): 281–285.CiteSeerX10.1.1.1006.6759.doi:10.1093/oxfordjournals.jbchem.a122261.PMID2836377.
- Yonezawa S, Maruyama I, Tanaka S, Nakamura T, Sato E (August 1988). "Immunohistochemical localization of thrombomodulin in chorionic diseases of the uterus and choriocarcinoma of the stomach. A comparative study with the distribution of human chorionic gonadotropin".Cancer.62(3): 569–576.doi:10.1002/1097-0142(19880801)62:3<569::AID-CNCR2820620322>3.0.CO;2-T.PMID2839283.S2CID28744944.
- Ishii H, Majerus PW (December 1985)."Thrombomodulin is present in human plasma and urine".The Journal of Clinical Investigation.76(6): 2178–2181.doi:10.1172/JCI112225.PMC424339.PMID3001144.
- Adler M, Seto MH, Nitecki DE, Lin JH, Light DR, Morser J (October 1995)."The structure of a 19-residue fragment from the C-loop of the fourth epidermal growth factor-like domain of thrombomodulin".The Journal of Biological Chemistry.270(40): 23366–23372.doi:10.1074/jbc.270.40.23366.PMID7559494.
- Ohlin AK, Marlar RA (January 1995)."The first mutation identified in the thrombomodulin gene in a 45-year-old man presenting with thromboembolic disease".Blood.85(2): 330–336.doi:10.1182/blood.V85.2.330.330.PMID7811989.
- Srinivasan J, Hu S, Hrabal R, Zhu Y, Komives EA, Ni F (November 1994). "Thrombin-bound structure of an EGF subdomain from human thrombomodulin determined by transferred nuclear Overhauser effects".Biochemistry.33(46): 13553–13560.doi:10.1021/bi00250a007.PMID7947766.
- Gerlitz B, Hassell T, Vlahos CJ, Parkinson JF, Bang NU, Grinnell BW (October 1993)."Identification of the predominant glycosaminoglycan-attachment site in soluble recombinant human thrombomodulin: potential regulation of functionality by glycosyltransferase competition for serine474".The Biochemical Journal.295(1): 131–140.doi:10.1042/bj2950131.PMC1134829.PMID8216207.
- Yasuda K, Espinosa R, Davis EM, Le Beau MM, Bell GI (September 1993). "Human somatostatin receptor genes: localization of SSTR5 to human chromosome 20p11.2".Genomics.17(3): 785–786.doi:10.1006/geno.1993.1410.PMID8244401.
- Yamamoto S, Mizoguchi T, Tamaki T, Ohkuchi M, Kimura S, Aoki N (April 1993). "Urinary thrombomodulin, its isolation and characterization".Journal of Biochemistry.113(4): 433–440.doi:10.1093/oxfordjournals.jbchem.a124063.PMID8390446.
- Meininger DP, Hunter MJ, Komives EA (September 1995)."Synthesis, activity, and preliminary structure of the fourth EGF-like domain of thrombomodulin".Protein Science.4(9): 1683–1695.doi:10.1002/pro.5560040904.PMC2143218.PMID8528067.
- Maglott DR,Feldblyum TV, Durkin AS, Nierman WC (May 1996). "Radiation hybrid mapping of SNAP, PCSK2, and THBD (human chromosome 20p)".Mammalian Genome.7(5): 400–401.doi:10.1007/s003359900120.PMID8661740.S2CID34951074.
External links
[edit]- GeneReviews/NCBI/NIH/UW entry on Atypical Hemolytic-Uremic Syndrome
- OMIM entries on Atypical Hemolytic-Uremic Syndrome
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