Trombomodulina
A trombomodulina (TM) ou CD141 ou BDCA-3 é unha proteína integral de membrana que se expresa na superficie das células endoteliais e funciona como cofactor para a trombina. Reduce a coagulación do sangue ao converter o encima procoagulante trombina nun encima anticoagulante.[1] A trombomodulina tamén se expresa nas células humanas mesoteliais,[2] monocitos e un subconxunto de células dendríticas.
Caracterización
[editar | editar a fonte]Nos humanos a trombomodulina está codificada no xene THBD [3] do cromosoma 20.[4] A proteína ten unha masa molecular de 74kDa, e consta dunha soa cadea con 5 dominios distintos. Na unión da trombomodulina coa trombina os contactos fundamentais son interaccións hidrofóbicas entre as cadeas laterais dos residuos Ile 414 e Ile 424 da trombomodulina e un peto hidrofóbico na superficie da trombina.
Función
[editar | editar a fonte]A trombomodulina é unha glicoproteína da superficie das células endoteliais que funciona como un cofactor na activación inducida pola trombina da proteína C na vía anticoagulante ao formar un complexo de estequiometría 1:1 coa trombina. Isto multiplica a velocidade de activación da proteína C por mil. A proteína C activada cliva os factores Va e VIIIa, que interveñen na produción de trombina, polo que esta produción diminúe.[3] Por tanto, o sistema trombina/trombomodulina/proteína C constitúe un control de retroalimentación negativa da produción de trombina.
A trombina unida á trombomodulina ten á vez un efecto inhibitorio da fibrinólise ao clivar o inhibidor da fibrinólise activable pola trombina (ou TAFI, tamén chamado carboxipeptidase B2) orixinando a súa forma activa.[5]
Ademais de unirse á trombina, a trombomodulina regula a inactivación de C3b (do sistema do complemento) polo factor I. As mutacións no xene da trombomodulina (THBD) tamén foron asociadas coa síndrome urémica hemolítica atípica.
Descubriuse que o antíxeno descrito inicialmente como BDCA-3 nas células dendríticas[6] en realidade é idéntico á trombomodulina.[7] Así, púxose en evidencia que esta molécula aparece nun subconxunto moi raro (0,02%) de células dendríticas humanas chamadas MDC2. A función que exerce nesas células non se coñece.
Interaccións
[editar | editar a fonte]A trombomudulina interacciona coa trombina.[8][9]
Notas
[editar | editar a fonte]- ↑ IPR001491 Thrombomodulin Acceso 22 agosto 2013.
- ↑ Verhagen HJ, Heijnen-Snyder GJ, Pronk A, Vroom TM, van Vroonhoven TJ, Eikelboom BC, Sixma JJ, de Groot PG. Thrombomodulin activity on mesothelial cells: perspectives for mesothelial cells as an alternative for endothelial cells for cell seeding on vascular grafts. Br J Haematol. 1996 Dec;95(3):542-9. PMID 8943899. [1]
- ↑ 3,0 3,1 OMIM
- ↑ Wen DZ, Dittman WA, Ye RD, Deaven LL, Majerus PW, Sadler JE (1987). "Human thrombomodulin: complete cDNA sequence and chromosome localization of the gene". Biochemistry 26 (14): 4350–7. PMID 2822087. doi:10.1021/bi00388a025.
- ↑ Zhao L, Morser J, Bajzar L, Nesheim M, Nagashima M (December 1998). "Identification and characterization of two thrombin-activatable fibrinolysis inhibitor isoforms". Thromb. Haemost. 80 (6): 949–55. PMID 9869166.
- ↑ Dzionek A, Fuchs A, Schmidt P, Cremer S, Zysk M, Miltenyi S, Buck DW, Schmitz J (2000). "BDCA-2, BDCA-3, and BDCA-4: three markers for distinct subsets of dendritic cells in human peripheral blood". J. Immunol. 165 (11): 6037–46. PMID 11086035.
- ↑ Dzionek A, Inagaki Y, Okawa K, Nagafune J, Röck J, Sohma Y, Winkels G, Zysk M, Yamaguchi Y, Schmitz J (2002). "Plasmacytoid dendritic cells: from specific surface markers to specific cellular functions". Hum. Immunol. 63 (12): 1133–48. PMID 12480257. doi:10.1016/S0198-8859(02)00752-8.
- ↑ Bajzar, L; Morser J, Nesheim M (1996). "TAFI, or plasma procarboxypeptidase B, couples the coagulation and fibrinolytic cascades through the thrombin-thrombomodulin complex". J. Biol. Chem. (UNITED STATES) 271 (28): 16603–8. ISSN 0021-9258. PMID 8663147. doi:10.1074/jbc.271.28.16603.
- ↑ Jakubowski, H V; Owen W G (1989). "Macromolecular specificity determinants on thrombin for fibrinogen and thrombomodulin". J. Biol. Chem. (UNITED STATES) 264 (19): 11117–21. ISSN 0021-9258. PMID 2544585.
Véxase tamén
[editar | editar a fonte]Bibliografía
[editar | editar a fonte]- Esmon CT (1995). "Thrombomodulin as a model of molecular mechanisms that modulate protease specificity and function at the vessel surface.". FASEB J. 9 (10): 946–55. PMID 7615164.
- Ohlin AK, Norlund L, Marlar RA (1997). "Thrombomodulin gene variations and thromboembolic disease.". Thromb. Haemost. 78 (1): 396–400. PMID 9198186.
- Van de Wouwer M, Collen D, Conway EM (2005). "Thrombomodulin-protein C-EPCR system: integrated to regulate coagulation and inflammation.". Arterioscler. Thromb. Vasc. Biol. 24 (8): 1374–83. PMID 15178554. doi:10.1161/01.ATV.0000134298.25489.92.
- Boffa MC, Jackman RW, Peyri N; et al. (1992). "Thrombomodulin in the central nervous system.". Nouvelle revue française d'hématologie 33 (6): 423–9. PMID 1667949.
- Jakubowski HV, Owen WG (1989). "Macromolecular specificity determinants on thrombin for fibrinogen and thrombomodulin.". J. Biol. Chem. 264 (19): 11117–21. PMID 2544585.
- Jackman RW, Beeler DL, Fritze L; et al. (1987). "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. 84 (18): 6425–9. PMC 299089. PMID 2819876. doi:10.1073/pnas.84.18.6425.
- Suzuki K, Kusumoto H, Deyashiki Y; et al. (1987). "Structure and expression of human thrombomodulin, a thrombin receptor on endothelium acting as a cofactor for protein C activation.". EMBO J. 6 (7): 1891–7. PMC 553573. PMID 2820710.
- Wen DZ, Dittman WA, Ye RD; et al. (1987). "Human thrombomodulin: complete cDNA sequence and chromosome localization of the gene.". Biochemistry 26 (14): 4350–7. PMID 2822087. doi:10.1021/bi00388a025.
- Shirai T, Shiojiri S, Ito H; et al. (1988). "Gene structure of human thrombomodulin, a cofactor for thrombin-catalyzed activation of protein C.". J. Biochem. 103 (2): 281–5. PMID 2836377.
- Yonezawa S, Maruyama I, Tanaka S; et al. (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. PMID 2839283. doi:10.1002/1097-0142(19880801)62:3<569::AID-CNCR2820620322>3.0.CO;2-T.
- Ishii H, Majerus PW (1986). "Thrombomodulin is present in human plasma and urine.". J. Clin. Invest. 76 (6): 2178–81. PMC 424339. PMID 3001144. doi:10.1172/JCI112225.
- Adler M, Seto MH, Nitecki DE; et al. (1995). "The structure of a 19-residue fragment from the C-loop of the fourth epidermal growth factor-like domain of thrombomodulin.". J. Biol. Chem. 270 (40): 23366–72. PMID 7559494. doi:10.1074/jbc.270.40.23366.
- Ohlin AK, Marlar RA (1995). "The first mutation identified in the thrombomodulin gene in a 45-year-old man presenting with thromboembolic disease.". Blood 85 (2): 330–6. PMID 7811989.
- Srinivasan J, Hu S, Hrabal R; et al. (1994). "Thrombin-bound structure of an EGF subdomain from human thrombomodulin determined by transferred nuclear Overhauser effects.". Biochemistry 33 (46): 13553–60. PMID 7947766. doi:10.1021/bi00250a007.
- Gerlitz B, Hassell T, Vlahos CJ; et al. (1993). "Identification of the predominant glycosaminoglycan-attachment site in soluble recombinant human thrombomodulin: potential regulation of functionality by glycosyltransferase competition for serine474.". Biochem. J. 295. ( Pt 1): 131–40. PMC 1134829. PMID 8216207.
- Yasuda K, Espinosa R, Davis EM; et al. (1993). "Human somatostatin receptor genes: localization of SSTR5 to human chromosome 20p11.2.". Genomics 17 (3): 785–6. PMID 8244401. doi:10.1006/geno.1993.1410.
- Yamamoto S, Mizoguchi T, Tamaki T; et al. (1993). "Urinary thrombomodulin, its isolation and characterization.". J. Biochem. 113 (4): 433–40. PMID 8390446.
- Meininger DP, Hunter MJ, Komives EA (1996). "Synthesis, activity, and preliminary structure of the fourth EGF-like domain of thrombomodulin.". Protein Sci. 4 (9): 1683–95. PMC 2143218. PMID 8528067. doi:10.1002/pro.5560040904.
- Maglott DR, Feldblyum TV, Durkin AS, Nierman WC (1996). "Radiation hybrid mapping of SNAP, PCSK2, and THBD (human chromosome 20p).". Mamm. Genome 7 (5): 400–1. PMID 8661740. doi:10.1007/s003359900120.
