Thrombomodulin

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.

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, BDCA-3
External IDs	OMIM: 188040; MGI: 98736; HomoloGene: 308; GeneCards: THBD; OMA:THBD - orthologs
Gene location (Human) Chr. Chromosome 20 (human) Band 20p11.21 Start 23,045,633 bp End 23,049,672 bp
Gene location (Mouse) Chr. Chromosome 2 (mouse) Band 2 G3|2 73.45 cM Start 148,246,386 bp End 148,250,108 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in gingival epithelium vena cava right lung skin of hip skin of abdomen skin of thigh periodontal fiber lower lobe of lung upper lobe of left lung left coronary artery Top expressed in right lung lobe left lung left lung lobe calvaria Gonadal ridge ankle aortic valve ascending aorta white adipose tissue decidua More reference expression data BioGPS More reference expression data
Gene ontology Molecular function calcium ion binding protein binding transmembrane signaling receptor activity signaling receptor activity Cellular component integral component of membrane cell surface plasma membrane integral component of plasma membrane membrane apicolateral plasma membrane vacuolar membrane extracellular space 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 signal transduction negative regulation of blood coagulation leukocyte migration Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 7056 21824 Ensembl ENSG00000178726 ENSMUSG00000074743 UniProt P07204 P15306 RefSeq (mRNA) NM_000361 NM_009378 RefSeq (protein) NP_000352 NP_033404 Location (UCSC) Chr 20: 23.05 – 23.05 Mb Chr 2: 148.25 – 148.25 Mb PubMed search
Wikidata
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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

• Esmon CT (July 1995). "Thrombomodulin as a model of molecular mechanisms that modulate protease specificity and function at the vessel surface". FASEB Journal. 9 (10): 946–955. doi:10.1096/fasebj.9.10.7615164. PMID 7615164. S2CID 19565674.
• Ohlin AK, Norlund L, Marlar RA (July 1997). "Thrombomodulin gene variations and thromboembolic disease". Thrombosis and Haemostasis. 78 (1): 396–400. doi:10.1055/s-0038-1657559. PMID 9198186. S2CID 25122238.
• Van de Wouwer M, Collen D, Conway EM (August 2004). "Thrombomodulin-protein C-EPCR system: integrated to regulate coagulation and inflammation". Arteriosclerosis, Thrombosis, and Vascular Biology. 24 (8): 1374–1383. 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): 423–429. PMID 1667949.
• Jackman RW, Beeler DL, Fritze L, Soff G, Rosenberg RD (September 1987). "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. 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, et al. (July 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): 1891–1897. doi:10.1002/j.1460-2075.1987.tb02448.x. PMC 553573. PMID 2820710.
• Wen DZ, Dittman WA, Ye RD, Deaven LL, Majerus PW, Sadler JE (July 1987). "Human thrombomodulin: complete cDNA sequence and chromosome localization of the gene". Biochemistry. 26 (14): 4350–4357. doi:10.1021/bi00388a025. PMID 2822087.
• Shirai T, Shiojiri S, Ito H, Yamamoto S, Kusumoto H, Deyashiki Y, et al. (February 1988). "Gene structure of human thrombomodulin, a cofactor for thrombin-catalyzed activation of protein C". Journal of Biochemistry. 103 (2): 281–285. CiteSeerX 10.1.1.1006.6759. doi:10.1093/oxfordjournals.jbchem.a122261. PMID 2836377.
• Yonezawa S, Maruyama I, Tanaka S, Nakamura T, Sato E (August 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): 569–576. doi:10.1002/1097-0142(19880801)62:3<569::AID-CNCR2820620322>3.0.CO;2-T. PMID 2839283. S2CID 28744944.
• Ishii H, Majerus PW (December 1985). "Thrombomodulin is present in human plasma and urine". The Journal of Clinical Investigation. 76 (6): 2178–2181. doi:10.1172/JCI112225. PMC 424339. PMID 3001144.
• Adler M, Seto MH, Nitecki DE, Lin JH, Light DR, Morser J (October 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): 23366–23372. doi:10.1074/jbc.270.40.23366. PMID 7559494.
• Ohlin AK, Marlar RA (January 1995). "The first mutation identified in the thrombomodulin gene in a 45-year-old man presenting with thromboembolic disease". Blood. 85 (2): 330–336. doi:10.1182/blood.V85.2.330.330. PMID 7811989.
• Srinivasan J, Hu S, Hrabal R, Zhu Y, Komives EA, Ni F (November 1994). "Thrombin-bound structure of an EGF subdomain from human thrombomodulin determined by transferred nuclear Overhauser effects". Biochemistry. 33 (46): 13553–13560. doi:10.1021/bi00250a007. PMID 7947766.
• Gerlitz B, Hassell T, Vlahos CJ, Parkinson JF, Bang NU, Grinnell BW (October 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): 131–140. doi:10.1042/bj2950131. PMC 1134829. PMID 8216207.
• Yasuda K, Espinosa R, Davis EM, Le Beau MM, Bell GI (September 1993). "Human somatostatin receptor genes: localization of SSTR5 to human chromosome 20p11.2". Genomics. 17 (3): 785–786. doi:10.1006/geno.1993.1410. PMID 8244401.
• Yamamoto S, Mizoguchi T, Tamaki T, Ohkuchi M, Kimura S, Aoki N (April 1993). "Urinary thrombomodulin, its isolation and characterization". Journal of Biochemistry. 113 (4): 433–440. doi:10.1093/oxfordjournals.jbchem.a124063. PMID 8390446.
• Meininger DP, Hunter MJ, Komives EA (September 1995). "Synthesis, activity, and preliminary structure of the fourth EGF-like domain of thrombomodulin". Protein Science. 4 (9): 1683–1695. 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. 7 (5): 400–401. doi:10.1007/s003359900120. PMID 8661740. S2CID 34951074.

External links

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