Thrombomodulin

Thrombomodulin

Thrombomodulin, CD141 or BDCA-3 is an integral membrane protein expressed on the surface of endothelial cells.

The protein has a molecular mass of 74kDa, and consists of a single chain with 5 distinct domains.

It 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 no procoagulant effect. The TT-complex also stimulates fibrinolysis by cleaving thrombin-activatable fibrinolysis inhibitor (TAFI) into its active form.

The antigen described as BDCA-3 [Dzionek, Andrzej; Fuchs,Anja; Schmidt, Petra; Cremer, Sabine; Zysk, Monika; Miltenyi, Stefan; Buck, David W. & Schmitz, Jürgen (2000): BDCA-2, BDCA-3, and BDCA-4: three markers for distinct subsets of dendritic cells in human peripheral blood. "Journal of Immuology" 165(11): 6037-6046. [http://www.jimmunol.org/cgi/reprint/165/11/6037.pdf PDF fulltext] ] has turned out to be identical to thrombomodulin. [Dzionek, Andrzej; Inagaki, Yoshimasa; Okawa, Katsuya; Nagafune, Jun; Röck, Jürgen; Sohma, Yoshiaki; Winkels, Gregor; Zysk, Monika; Yamaguchi, Yasunori & Schmitz, Jürgen (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 (HTML abstract)] 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 at present, but apparently, thrombomodulin has at least one other ligand apart from thrombin, because anticoaglulation is a commonplace function, in contrast to the rarity of MDC2 cells.

References

Further reading

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citations =
*cite journal | author=Esmon CT |title=Thrombomodulin as a model of molecular mechanisms that modulate protease specificity and function at the vessel surface. |journal=FASEB J. |volume=9 |issue= 10 |pages= 946–55 |year= 1995 |pmid= 7615164 |doi=
*cite journal | author=Ohlin AK, Norlund L, Marlar RA |title=Thrombomodulin gene variations and thromboembolic disease. |journal=Thromb. Haemost. |volume=78 |issue= 1 |pages= 396–400 |year= 1997 |pmid= 9198186 |doi=
*cite journal | author=Van de Wouwer M, Collen D, Conway EM |title=Thrombomodulin-protein C-EPCR system: integrated to regulate coagulation and inflammation. |journal=Arterioscler. Thromb. Vasc. Biol. |volume=24 |issue= 8 |pages= 1374–83 |year= 2005 |pmid= 15178554 |doi= 10.1161/01.ATV.0000134298.25489.92
*cite journal | author=Boffa MC, Jackman RW, Peyri N, "et al." |title=Thrombomodulin in the central nervous system. |journal=Nouvelle revue française d'hématologie |volume=33 |issue= 6 |pages= 423–9 |year= 1992 |pmid= 1667949 |doi=
*cite journal | author=Jakubowski HV, Owen WG |title=Macromolecular specificity determinants on thrombin for fibrinogen and thrombomodulin. |journal=J. Biol. Chem. |volume=264 |issue= 19 |pages= 11117–21 |year= 1989 |pmid= 2544585 |doi=
*cite journal | author=Jackman RW, Beeler DL, Fritze L, "et al." |title=Human thrombomodulin gene is intron depleted: nucleic acid sequences of the cDNA and gene predict protein structure and suggest sites of regulatory control. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=84 |issue= 18 |pages= 6425–9 |year= 1987 |pmid= 2819876 |doi=
*cite journal | author=Suzuki K, Kusumoto H, Deyashiki Y, "et al." |title=Structure and expression of human thrombomodulin, a thrombin receptor on endothelium acting as a cofactor for protein C activation. |journal=EMBO J. |volume=6 |issue= 7 |pages= 1891–7 |year= 1987 |pmid= 2820710 |doi=
*cite journal | author=Wen DZ, Dittman WA, Ye RD, "et al." |title=Human thrombomodulin: complete cDNA sequence and chromosome localization of the gene. |journal=Biochemistry |volume=26 |issue= 14 |pages= 4350–7 |year= 1987 |pmid= 2822087 |doi=
*cite journal | author=Shirai T, Shiojiri S, Ito H, "et al." |title=Gene structure of human thrombomodulin, a cofactor for thrombin-catalyzed activation of protein C. |journal=J. Biochem. |volume=103 |issue= 2 |pages= 281–5 |year= 1988 |pmid= 2836377 |doi=
*cite journal | author=Yonezawa S, Maruyama I, Tanaka S, "et al." |title=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. |journal=Cancer |volume=62 |issue= 3 |pages= 569–76 |year= 1988 |pmid= 2839283 |doi=
*cite journal | author=Ishii H, Majerus PW |title=Thrombomodulin is present in human plasma and urine. |journal=J. Clin. Invest. |volume=76 |issue= 6 |pages= 2178–81 |year= 1986 |pmid= 3001144 |doi=
*cite journal | author=Adler M, Seto MH, Nitecki DE, "et al." |title=The structure of a 19-residue fragment from the C-loop of the fourth epidermal growth factor-like domain of thrombomodulin. |journal=J. Biol. Chem. |volume=270 |issue= 40 |pages= 23366–72 |year= 1995 |pmid= 7559494 |doi=
*cite journal | author=Ohlin AK, Marlar RA |title=The first mutation identified in the thrombomodulin gene in a 45-year-old man presenting with thromboembolic disease. |journal=Blood |volume=85 |issue= 2 |pages= 330–6 |year= 1995 |pmid= 7811989 |doi=
*cite journal | author=Srinivasan J, Hu S, Hrabal R, "et al." |title=Thrombin-bound structure of an EGF subdomain from human thrombomodulin determined by transferred nuclear Overhauser effects. |journal=Biochemistry |volume=33 |issue= 46 |pages= 13553–60 |year= 1994 |pmid= 7947766 |doi=
*cite journal | author=Gerlitz B, Hassell T, Vlahos CJ, "et al." |title=Identification of the predominant glycosaminoglycan-attachment site in soluble recombinant human thrombomodulin: potential regulation of functionality by glycosyltransferase competition for serine474. |journal=Biochem. J. |volume=295 ( Pt 1) |issue= |pages= 131–40 |year= 1993 |pmid= 8216207 |doi=
*cite journal | author=Yasuda K, Espinosa R, Davis EM, "et al." |title=Human somatostatin receptor genes: localization of SSTR5 to human chromosome 20p11.2. |journal=Genomics |volume=17 |issue= 3 |pages= 785–6 |year= 1993 |pmid= 8244401 |doi= 10.1006/geno.1993.1410
*cite journal | author=Yamamoto S, Mizoguchi T, Tamaki T, "et al." |title=Urinary thrombomodulin, its isolation and characterization. |journal=J. Biochem. |volume=113 |issue= 4 |pages= 433–40 |year= 1993 |pmid= 8390446 |doi=
*cite journal | author=Meininger DP, Hunter MJ, Komives EA |title=Synthesis, activity, and preliminary structure of the fourth EGF-like domain of thrombomodulin. |journal=Protein Sci. |volume=4 |issue= 9 |pages= 1683–95 |year= 1996 |pmid= 8528067 |doi=
*cite journal | author=Maglott DR, Feldblyum TV, Durkin AS, Nierman WC |title=Radiation hybrid mapping of SNAP, PCSK2, and THBD (human chromosome 20p). |journal=Mamm. Genome |volume=7 |issue= 5 |pages= 400–1 |year= 1996 |pmid= 8661740 |doi=

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