Thrombomodulin

THBD
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1ADX, 1DQB, 1DX5, 1EGT, 1FGD, 1FGE, 1HLT, 1TMR, 1ZAQ, 2ADX, 3GIS
Identifiers
Aliases	THBD, AHUS6, BDCA3, CD141, THPH12, THRM, TM, thrombomodulin
External IDs	OMIM: 188040 MGI: 98736 HomoloGene: 308 GeneCards: THBD
Gene ontology Molecular function • calcium ion binding • protein binding • transmembrane signaling receptor activity • receptor activity Cellular component • extracellular fluid • integral component of membrane • cell surface • plasma membrane • integral component of plasma membrane • membrane • apicolateral plasma membrane • vacuolar membrane Biological process • hemostasis • female pregnancy • negative regulation of platelet activation • response to lipopolysaccharide • response to cAMP • negative regulation of fibrinolysis • blood coagulation • response to X-ray • leukocyte migration • signal transduction • negative regulation of blood coagulation Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	7056	21824
Ensembl	ENSG00000178726	ENSMUSG00000074743
UniProt	P07204	P15306
RefSeq (mRNA)	NM_000361	NM_009378
RefSeq (protein)	NP_000352.1	NP_033404.1
Location (UCSC)	Chr 20: 23.05 – 23.05 Mb	Chr 2: 148.4 – 148.41 Mb
PubMed search	[1]	[2]
Wikidata

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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.^[3] Thrombomodulin is also expressed on human mesothelial cell,^[4] monocyte and a dendritic cell subset.

Genetics and Structure

In humans, thrombomodulin is encoded by the THBD gene.^[5] 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.^[6]

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^[7] has turned out to be identical to thrombomodulin.^[8] 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.^[9][10]

References

1. "Human PubMed Reference:".
2. "Mouse PubMed Reference:".
3. IPR001491 Thrombomodulin Accessed January 19, 2012.
4. 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. PMID 8943899.
5. 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. PMID 2822087.
6. Sadler JE (Jul 1997). "Thrombomodulin structure and function". Thrombosis and haemostasis. 78 (1): 392–5. PMID 9198185.
7. 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 (Baltimore, Md. : 1950). 165 (11): 6037–46. doi:10.4049/jimmunol.165.11.6037. PMID 11086035.
8. 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. PMID 12480257.
9. 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. PMID 8663147.
10. Jakubowski HV, Owen WG (Jul 1989). "Macromolecular specificity determinants on thrombin for fibrinogen and thrombomodulin". The Journal of Biological Chemistry. 264 (19): 11117–21. PMID 2544585.

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. PMID 7615164.
• Ohlin AK, Norlund L, Marlar RA (Jul 1997). "Thrombomodulin gene variations and thromboembolic disease". Thrombosis and Haemostasis. 78 (1): 396–400. PMID 9198186.
• 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. PMID 15178554.
• 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. PMID 1667949.
• Jackman RW, Beeler DL, Fritze L, Soff G, Rosenberg RD (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. Bibcode:1987PNAS...84.6425J. doi:10.1073/pnas.84.18.6425. PMC 299089. PMID 2819876.
• Suzuki K, Kusumoto H, Deyashiki Y, Nishioka J, Maruyama I, Zushi M, Kawahara S, Honda G, Yamamoto S, Horiguchi S (Jul 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): 1891–7. PMC 553573. PMID 2820710.
• 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. PMID 2822087.
• 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. PMID 2836377.
• 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. PMID 2839283.
• Ishii H, Majerus PW (Dec 1985). "Thrombomodulin is present in human plasma and urine". The Journal of Clinical Investigation. 76 (6): 2178–81. doi:10.1172/JCI112225. PMC 424339. PMID 3001144.
• 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. PMID 7559494.
• 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. PMID 7811989.
• 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. PMID 7947766.
• Gerlitz B, Hassell T, Vlahos CJ, Parkinson JF, Bang NU, Grinnell BW (Oct 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): 131–40. doi:10.1042/bj2950131. PMC 1134829. PMID 8216207.
• 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. PMID 8244401.
• Yamamoto S, Mizoguchi T, Tamaki T, Ohkuchi M, Kimura S, Aoki N (Apr 1993). "Urinary thrombomodulin, its isolation and characterization". Journal of Biochemistry. 113 (4): 433–40. PMID 8390446.
• Meininger DP, Hunter MJ, Komives EA (Sep 1995). "Synthesis, activity, and preliminary structure of the fourth EGF-like domain of thrombomodulin". Protein Science : A Publication of the Protein Society. 4 (9): 1683–95. doi:10.1002/pro.5560040904. PMC 2143218. PMID 8528067.
• Maglott DR, Feldblyum TV, Durkin AS, Nierman WC (May 1996). "Radiation hybrid mapping of SNAP, PCSK2, and THBD (human chromosome 20p)". Mammalian Genome : Official Journal of the International Mammalian Genome Society. 7 (5): 400–1. 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