Biology:Thrombomodulin

Generic protein structure example

Thrombomodulin (TM), CD141 or BDCA-3 is an integral membrane protein expressed on the surface of endothelial cells and serves as a cofactor for thrombin. It reduces blood coagulation by converting thrombin to an anticoagulant enzyme from a procoagulant enzyme. Thrombomodulin is also expressed on human mesothelial cell, monocyte and a dendritic cell subset.

Genetics and structure

In humans, thrombomodulin is encoded by the THBD gene. 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. It is a member of the C-type lectin domain (CTLD) group 14 family.

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.

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).

The antigen described as BDCA-3 has turned out to be identical to thrombomodulin. 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.

Interactions

Thrombomodulin has been shown to interact with thrombin.

Further reading

• "Thrombomodulin as a model of molecular mechanisms that modulate protease specificity and function at the vessel surface". FASEB Journal 9 (10): 946–955. July 1995. doi:10.1096/fasebj.9.10.7615164. PMID 7615164. 
• "Thrombomodulin gene variations and thromboembolic disease". Thrombosis and Haemostasis 78 (1): 396–400. July 1997. doi:10.1055/s-0038-1657559. PMID 9198186. 
• "Thrombomodulin-protein C-EPCR system: integrated to regulate coagulation and inflammation". Arteriosclerosis, Thrombosis, and Vascular Biology 24 (8): 1374–1383. August 2004. doi:10.1161/01.ATV.0000134298.25489.92. PMID 15178554. 
• "Thrombomodulin in the central nervous system". Nouvelle Revue Française d'Hématologie 33 (6): 423–429. 1991. PMID 1667949. 
• "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. September 1987. doi:10.1073/pnas.84.18.6425. PMID 2819876. Bibcode: 1987PNAS...84.6425J. 
• "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. July 1987. doi:10.1002/j.1460-2075.1987.tb02448.x. PMID 2820710. 
• "Human thrombomodulin: complete cDNA sequence and chromosome localization of the gene". Biochemistry 26 (14): 4350–4357. July 1987. doi:10.1021/bi00388a025. PMID 2822087. 
• "Gene structure of human thrombomodulin, a cofactor for thrombin-catalyzed activation of protein C". Journal of Biochemistry 103 (2): 281–285. February 1988. doi:10.1093/oxfordjournals.jbchem.a122261. PMID 2836377. 
• "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. August 1988. doi:10.1002/1097-0142(19880801)62:3<569::AID-CNCR2820620322>3.0.CO;2-T. PMID 2839283. 
• "Thrombomodulin is present in human plasma and urine". The Journal of Clinical Investigation 76 (6): 2178–2181. December 1985. doi:10.1172/JCI112225. PMID 3001144. 
• "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. October 1995. doi:10.1074/jbc.270.40.23366. PMID 7559494. 
• "The first mutation identified in the thrombomodulin gene in a 45-year-old man presenting with thromboembolic disease". Blood 85 (2): 330–336. January 1995. doi:10.1182/blood.V85.2.330.330. PMID 7811989. 
• "Thrombin-bound structure of an EGF subdomain from human thrombomodulin determined by transferred nuclear Overhauser effects". Biochemistry 33 (46): 13553–13560. November 1994. doi:10.1021/bi00250a007. PMID 7947766. 
• "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. October 1993. doi:10.1042/bj2950131. PMID 8216207. 
• "Human somatostatin receptor genes: localization of SSTR5 to human chromosome 20p11.2". Genomics 17 (3): 785–786. September 1993. doi:10.1006/geno.1993.1410. PMID 8244401. 
• "Urinary thrombomodulin, its isolation and characterization". Journal of Biochemistry 113 (4): 433–440. April 1993. doi:10.1093/oxfordjournals.jbchem.a124063. PMID 8390446. 
• "Synthesis, activity, and preliminary structure of the fourth EGF-like domain of thrombomodulin". Protein Science 4 (9): 1683–1695. September 1995. doi:10.1002/pro.5560040904. PMID 8528067. 
• "Radiation hybrid mapping of SNAP, PCSK2, and THBD (human chromosome 20p)". Mammalian Genome 7 (5): 400–401. May 1996. doi:10.1007/s003359900120. PMID 8661740. 

External links

• GeneReviews/NCBI/NIH/UW entry on Atypical Hemolytic-Uremic Syndrome
• OMIM entries on Atypical Hemolytic-Uremic Syndrome