Thrombomodulin

Last updated
THBD
Protein THBD PDB 1adx.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases THBD , AHUS6, BDCA3, CD141, THPH12, THRM, TM, thrombomodulin, BDCA-3
External IDs OMIM: 188040 MGI: 98736 HomoloGene: 308 GeneCards: THBD
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_000361

NM_009378

RefSeq (protein)

NP_000352

NP_033404

Location (UCSC) Chr 20: 23.05 – 23.05 Mb Chr 2: 148.4 – 148.41 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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. [5] Thrombomodulin is also expressed on human mesothelial cell, [6] monocyte and a dendritic cell subset.

Genetics and structure

In humans, thrombomodulin is encoded by the THBD gene. [7] 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. [8] It is a member of the C-type lectin domain (CTLD) group 14 family. [9]

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.[ citation needed ]

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). [10]

The antigen described as BDCA-3 [11] has turned out to be identical to thrombomodulin. [12] 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.[ citation needed ]

Interactions

Thrombomodulin has been shown to interact with thrombin. [13] [14]

Related Research Articles

Thrombin Enzyme in humans

Thrombin is a serine protease, an enzyme that, in humans, is encoded by the F2 gene. Prothrombin is proteolytically cleaved to form thrombin in the clotting process. Thrombin in turn acts as a serine protease that converts soluble fibrinogen into insoluble strands of fibrin, as well as catalyzing many other coagulation-related reactions.

Hemolytic–uremic syndrome Group of blood disorders related to bacterial infection

Hemolytic–uremic syndrome (HUS) is a group of blood disorders characterized by low red blood cells, acute kidney failure, and low platelets. Initial symptoms typically include bloody diarrhea, fever, vomiting, and weakness. Kidney problems and low platelets then occur as the diarrhea progresses. Children are more commonly affected, but most children recover without permanent damage to their health, although some children may have serious and sometimes life-threatening complications. Adults, specially the elderly, may present a more complicated presentation. Complications may include neurological problems and heart failure.

Factor IX

Factor IX is one of the serine proteases of the coagulation system; it belongs to peptidase family S1. Deficiency of this protein causes haemophilia B. It was discovered in 1952 after a young boy named Stephen Christmas was found to be lacking this exact factor, leading to haemophilia.

Protein S

Protein S is a vitamin K-dependent plasma glycoprotein synthesized in the liver. In the circulation, Protein S exists in two forms: a free form and a complex form bound to complement protein C4b-binding protein (C4BP). In humans, protein S is encoded by the PROS1 gene. Protein S plays a role in coagulation.

Protein C Mammalian protein found in Homo sapiens

Protein C, also known as autoprothrombin IIA and blood coagulation factor XIX, is a zymogen, the activated form of which plays an important role in regulating anticoagulation, inflammation, and cell death and maintaining the permeability of blood vessel walls in humans and other animals. Activated protein C (APC) performs these operations primarily by proteolytically inactivating proteins Factor Va and Factor VIIIa. APC is classified as a serine protease since it contains a residue of serine in its active site. In humans, protein C is encoded by the PROC gene, which is found on chromosome 2.

Factor X

Factor X, also known by the eponym Stuart–Prower factor, is an enzyme of the coagulation cascade. It is a serine endopeptidase. Factor X is synthesized in the liver and requires vitamin K for its synthesis.

Complement component 3

Complement component 3, often simply called C3, is a protein of the immune system. It plays a central role in the complement system and contributes to innate immunity. In humans it is encoded on chromosome 19 by a gene called C3.

The prothrombinase complex consists of the serine protease, Factor Xa, and the protein cofactor, Factor Va. The complex assembles on negatively charged phospholipid membranes in the presence of calcium ions. The prothrombinase complex catalyzes the conversion of prothrombin (Factor II), an inactive zymogen, to thrombin (Factor IIa), an active serine protease. The activation of thrombin is a critical reaction in the coagulation cascade, which functions to regulate hemostasis in the body. To produce thrombin, the prothrombinase complex cleaves two peptide bonds in prothrombin, one after Arg271 and the other after Arg320. Although it has been shown that Factor Xa can activate prothrombin when unassociated with the prothrombinase complex, the rate of thrombin formation is severely decreased under such circumstances. The prothrombinase complex can catalyze the activation of prothrombin at a rate 3 x 105-fold faster than can Factor Xa alone. Thus, the prothrombinase complex is required for the efficient production of activated thrombin and also for adequate hemostasis.

Complement factor B

Complement factor B is a protein that in humans is encoded by the CFB gene.

Heparin cofactor II

Heparin cofactor II (HCII), a protein encoded by the SERPIND1 gene, is a coagulation factor that inhibits IIa, and is a cofactor for heparin and dermatan sulfate.

Factor H

Factor H is a member of the regulators of complement activation family and is a complement control protein. It is a large, soluble glycoprotein that circulates in human plasma. Its principal function is to regulate the alternative pathway of the complement system, ensuring that the complement system is directed towards pathogens or other dangerous material and does not damage host tissue. Factor H regulates complement activation on self cells and surfaces by possessing both cofactor activity for the Factor I mediated C3b cleavage, and decay accelerating activity against the alternative pathway C3-convertase, C3bBb. Factor H exerts its protective action on self cells and self surfaces but not on the surfaces of bacteria or viruses. This is thought to be the result of Factor H having the ability to adopt conformations with lower or higher activities as a cofactor for C3 cleavage or decay accelerating activity. The lower activity conformation is the predominant form in solution and is sufficient to control fluid phase amplification. The more active conformation is thought to be induced when Factor H binds to glycosaminoglycans (GAGs) and or sialic acids that are generally present on host cells but not, normally, on pathogen surfaces ensuring that self surfaces are protected whilst complement proceeds unabated on foreign surfaces.

CD46

CD46 complement regulatory protein also known as CD46 and Membrane Cofactor Protein is a protein which in humans is encoded by the CD46 gene. CD46 is an inhibitory complement receptor.

Complement factor I Protein

Complement factor I, also known as C3b/C4b inactivator, is a protein that in humans is encoded by the CFI gene. Complement factor I is a protein of the complement system, first isolated in 1966 in guinea pig serum, that regulates complement activation by cleaving cell-bound or fluid phase C3b and C4b. It is a soluble glycoprotein that circulates in human blood at an average concentration of 35 μg/mL.

EMR3

EGF-like module-containing mucin-like hormone receptor-like 3 is a protein encoded by the ADGRE3 gene. EMR3 is a member of the adhesion GPCR family. Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.

F2RL2

Protease activated receptor 3 (PAR-3) also known as coagulation factor II receptor-like 2 (F2RL2) and thrombin receptor-like 2, is a protein that in humans is encoded by the F2RL2 gene.

EGF-like domain Protein domain named after the epidermal growth factor protein

The EGF-like domain is an evolutionary conserved protein domain, which derives its name from the epidermal growth factor where it was first described. It comprises about 30 to 40 amino-acid residues and has been found in a large number of mostly animal proteins. Most occurrences of the EGF-like domain are found in the extracellular domain of membrane-bound proteins or in proteins known to be secreted. An exception to this is the prostaglandin-endoperoxide synthase. The EGF-like domain includes 6 cysteine residues which in the epidermal growth factor have been shown to form 3 disulfide bonds. The structures of 4-disulfide EGF-domains have been solved from the laminin and integrin proteins. The main structure of EGF-like domains is a two-stranded β-sheet followed by a loop to a short C-terminal, two-stranded β-sheet. These two β-sheets are usually denoted as the major (N-terminal) and minor (C-terminal) sheets. EGF-like domains frequently occur in numerous tandem copies in proteins: these repeats typically fold together to form a single, linear solenoid domain block as a functional unit.

Carboxypeptidase B2

Carboxypeptidase B2 (CPB2), also known as carboxypeptidase U (CPU), plasma carboxypeptidase B (pCPB) or thrombin-activatable fibrinolysis inhibitor (TAFI), is an enzyme that, in humans, is encoded by the gene CPB2.

CFHR1

Complement factor H-related protein 1 is a protein that in humans is encoded by the CFHR1 gene.

CFHR3

Complement factor H-related protein 3 is a protein that in humans is encoded by the CFHR3 gene.

Atypical hemolytic uremic syndrome (aHUS) is an extremely rare, life-threatening, progressive disease that frequently has a genetic component. In most cases it can be effectively controlled by interruption of the complement cascade. Particular monoclonal antibodies, discussed later in the article, have proven efficacy in many cases.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000178726 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000074743 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. IPR001491 Thrombomodulin Accessed January 19, 2012.
  6. Verhagen HJ, Heijnen-Snyder GJ, Pronk A, Vroom TM, van Vroonhoven TJ, Eikelboom BC, et al. (December 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): 542–549. doi:10.1046/j.1365-2141.1996.d01-1935.x. PMID   8943899. S2CID   8417511.
  7. 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.
  8. Sadler JE (July 1997). "Thrombomodulin structure and function". Thrombosis and Haemostasis. 78 (1): 392–395. doi:10.1055/s-0038-1657558. PMID   9198185.
  9. Khan KA, McMurray JL, Mohammed F, Bicknell R (September 2019). "C-type lectin domain group 14 proteins in vascular biology, cancer and inflammation". The FEBS Journal. 286 (17): 3299–3332. doi:10.1111/febs.14985. PMC   6852297 . PMID   31287944.
  10. Delvaeye M, Noris M, De Vriese A, Esmon CT, Esmon NL, Ferrell G, et al. (July 2009). "Thrombomodulin mutations in atypical hemolytic-uremic syndrome". The New England Journal of Medicine. 361 (4): 345–357. doi:10.1056/NEJMoa0810739. PMC   3530919 . PMID   19625716.
  11. Dzionek A, Fuchs A, Schmidt P, Cremer S, Zysk M, Miltenyi S, et al. (December 2000). "BDCA-2, BDCA-3, and BDCA-4: three markers for distinct subsets of dendritic cells in human peripheral blood". Journal of Immunology. 165 (11): 6037–6046. doi: 10.4049/jimmunol.165.11.6037 . PMID   11086035.
  12. Dzionek A, Inagaki Y, Okawa K, Nagafune J, Röck J, Sohma Y, et al. (December 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. PMID   12480257.
  13. Bajzar L, Morser J, Nesheim M (July 1996). "TAFI, or plasma procarboxypeptidase B, couples the coagulation and fibrinolytic cascades through the thrombin-thrombomodulin complex". The Journal of Biological Chemistry. 271 (28): 16603–16608. doi: 10.1074/jbc.271.28.16603 . PMID   8663147.
  14. Jakubowski HV, Owen WG (July 1989). "Macromolecular specificity determinants on thrombin for fibrinogen and thrombomodulin". The Journal of Biological Chemistry. 264 (19): 11117–11121. doi: 10.1016/S0021-9258(18)60437-5 . PMID   2544585.

Further reading