In humans, thrombomodulin is encoded by the THBDgene.[3] The protein has a molecular mass of 74kDa, and consists of a single chain with six tandemly repeated EGF-like domains, a Serine/Threonine-rich spacer and a transmembrane domain.[4]
Function
Thrombomodulin functions as a cofactor in the thrombin-induced activation of protein C in the anticoagulant pathway 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 cleaving thrombin-activatable fibrinolysis inhibitor (TAFI, aka carboxypeptidase B2) into its active form.[citation needed]
Thrombomodulin is a glycoprotein on the surface of endothelial cells that, in addition to binding thrombin, regulates C3b inactivation by factor I. Mutations in the thrombomodulin gene (THBD) have also been reported to be associated with atypical hemolytic-uremic syndrome (aHUS).[citation needed]
The antigen described as BDCA-3[5] has turned out to be identical to thrombomodulin.[6] Thus, it was revealed that this molecule also occurs on a very rare (0.02%) subset of human dendritic cells called MDC2. Its function on these cells is unknown.[citation needed]
↑Verhagen HJ, Heijnen-Snyder GJ, Pronk A, Vroom TM, van Vroonhoven TJ, Eikelboom BC, Sixma JJ, de Groot PG (Dec 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): 542–9. doi:10.1046/j.1365-2141.1996.d01-1935.x. PMID8943899.
↑Wen DZ, Dittman WA, Ye RD, Deaven LL, Majerus PW, Sadler JE (Jul 1987). "Human thrombomodulin: complete cDNA sequence and chromosome localization of the gene". Biochemistry. 26 (14): 4350–7. doi:10.1021/bi00388a025. PMID2822087.
↑Sadler JE (Jul 1997). "Thrombomodulin structure and function". Thrombosis and Haemostasis. 78 (1): 392–5. PMID9198185.
↑Dzionek A, Fuchs A, Schmidt P, Cremer S, Zysk M, Miltenyi S, Buck DW, Schmitz J (Dec 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): 6037–46. doi:10.4049/jimmunol.165.11.6037. PMID11086035.
↑Dzionek A, Inagaki Y, Okawa K, Nagafune J, Röck J, Sohma Y, Winkels G, Zysk M, Yamaguchi Y, Schmitz J (Dec 2002). "Plasmacytoid dendritic cells: from specific surface markers to specific cellular functions". Human Immunology. 63 (12): 1133–48. doi:10.1016/S0198-8859(02)00752-8. PMID12480257.
↑Bajzar L, Morser J, Nesheim M (Jul 1996). "TAFI, or plasma procarboxypeptidase B, couples the coagulation and fibrinolytic cascades through the thrombin-thrombomodulin complex". The Journal of Biological Chemistry. 271 (28): 16603–8. doi:10.1074/jbc.271.28.16603. PMID8663147.
↑Jakubowski HV, Owen WG (Jul 1989). "Macromolecular specificity determinants on thrombin for fibrinogen and thrombomodulin". The Journal of Biological Chemistry. 264 (19): 11117–21. PMID2544585.
Further reading
Esmon CT (Jul 1995). "Thrombomodulin as a model of molecular mechanisms that modulate protease specificity and function at the vessel surface". FASEB Journal. 9 (10): 946–55. PMID7615164.
Ohlin AK, Norlund L, Marlar RA (Jul 1997). "Thrombomodulin gene variations and thromboembolic disease". Thrombosis and Haemostasis. 78 (1): 396–400. PMID9198186.
Van de Wouwer M, Collen D, Conway EM (Aug 2004). "Thrombomodulin-protein C-EPCR system: integrated to regulate coagulation and inflammation". Arteriosclerosis, Thrombosis, and Vascular Biology. 24 (8): 1374–83. 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): 423–9. PMID1667949.
Wen DZ, Dittman WA, Ye RD, Deaven LL, Majerus PW, Sadler JE (Jul 1987). "Human thrombomodulin: complete cDNA sequence and chromosome localization of the gene". Biochemistry. 26 (14): 4350–7. doi:10.1021/bi00388a025. PMID2822087.
Shirai T, Shiojiri S, Ito H, Yamamoto S, Kusumoto H, Deyashiki Y, Maruyama I, Suzuki K (Feb 1988). "Gene structure of human thrombomodulin, a cofactor for thrombin-catalyzed activation of protein C". Journal of Biochemistry. 103 (2): 281–5. PMID2836377.
Yonezawa S, Maruyama I, Tanaka S, Nakamura T, Sato E (Aug 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): 569–76. doi:10.1002/1097-0142(19880801)62:3<569::AID-CNCR2820620322>3.0.CO;2-T. PMID2839283.
Adler M, Seto MH, Nitecki DE, Lin JH, Light DR, Morser J (Oct 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): 23366–72. doi:10.1074/jbc.270.40.23366. PMID7559494.
Ohlin AK, Marlar RA (Jan 1995). "The first mutation identified in the thrombomodulin gene in a 45-year-old man presenting with thromboembolic disease". Blood. 85 (2): 330–6. PMID7811989.
Srinivasan J, Hu S, Hrabal R, Zhu Y, Komives EA, Ni F (Nov 1994). "Thrombin-bound structure of an EGF subdomain from human thrombomodulin determined by transferred nuclear Overhauser effects". Biochemistry. 33 (46): 13553–60. doi:10.1021/bi00250a007. PMID7947766.
Yasuda K, Espinosa R, Davis EM, Le Beau MM, Bell GI (Sep 1993). "Human somatostatin receptor genes: localization of SSTR5 to human chromosome 20p11.2". Genomics. 17 (3): 785–6. doi:10.1006/geno.1993.1410. PMID8244401.
