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
External IDs OMIM: 188040 MGI: 98736 HomoloGene: 308 GeneCards: THBD
Gene location (Human)
Ideogram human chromosome 20.svg
Chr. Chromosome 20 (human) [1]
Human chromosome 20 ideogram.svg
HSR 1996 II 3.5e.svg
Red rectangle 2x18.png
Band 20p11.21Start23,045,633 bp [1]
End23,049,672 bp [1]
RNA expression pattern
PBB GE THBD 203888 at fs.png

PBB GE THBD 203887 s at fs.png
More reference expression data
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).[ citation needed ]

The antigen described as BDCA-3 [10] has turned out to be identical to thrombomodulin. [11] 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. [12] [13]

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.

Factor VIII

Factor VIII (FVIII) is an essential blood-clotting protein, also known as anti-hemophilic factor (AHF). In humans, factor VIII is encoded by the F8 gene. Defects in this gene result in hemophilia A, a recessive X-linked coagulation disorder. Factor VIII is produced in liver sinusoidal cells and endothelial cells outside the liver throughout the body. This protein circulates in the bloodstream in an inactive form, bound to another molecule called von Willebrand factor, until an injury that damages blood vessels occurs. In response to injury, coagulation factor VIII is activated and separates from von Willebrand factor. The active protein interacts with another coagulation factor called factor IX. This interaction sets off a chain of additional chemical reactions that form a blood clot.

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 C

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.

Factor XI

Factor XI or plasma thromboplastin antecedent is the zymogen form of factor XIa, one of the enzymes of the coagulation cascade. Like many other coagulation factors, it is a serine protease. In humans, Factor XI is encoded by the F11 gene.

Histamine H<sub>1</sub> receptor

The H1 receptor is a histamine receptor belonging to the family of rhodopsin-like G-protein-coupled receptors. This receptor is activated by the biogenic amine histamine. It is expressed in smooth muscles, on vascular endothelial cells, in the heart, and in the central nervous system. The H1 receptor is linked to an intracellular G-protein (Gq) that activates phospholipase C and the inositol triphosphate (IP3) signalling pathway. Antihistamines, which act on this receptor, are used as anti-allergy drugs. The crystal structure of the receptor has been determined (shown on the right) and used to discover new histamine H1 receptor ligands in structure-based virtual screening studies.

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.

Protein C inhibitor

Protein C inhibitor is a serine protease inhibitor (serpin) that limits the activity of protein C.

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.

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.

SHC1

SHC-transforming protein 1 is a protein that in humans is encoded by the SHC1 gene. SHC has been found to be important in the regulation of apoptosis and drug resistance in mammalian cells.

RAB5A

Ras-related protein Rab-5A is a protein that in humans is encoded by the RAB5A gene.

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.

KARS (gene)

Lysyl-tRNA synthetase is an enzyme that in humans is encoded by the KARS gene.

CFHR1

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

LAG3

Lymphocyte-activation gene 3, also known as LAG-3, is a protein which in humans is encoded by the LAG3 gene. LAG3, which was discovered in 1990 and was designated CD223 after the Seventh Human Leucocyte Differentiation Antigen Workshop in 2000, is a cell surface molecule with diverse biologic effects on T cell function. It is an immune checkpoint receptor and as such is the target of various drug development programs by pharmaceutical companies seeking to develop new treatments for cancer and autoimmune disorders. In soluble form it is also being developed as a cancer drug in its own right.

NRD1

Nardilysin is a protein that in humans is encoded by the NRD1 gene.

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, 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. S2CID   8417511.
  7. 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.
  8. Sadler JE (Jul 1997). "Thrombomodulin structure and function". Thrombosis and Haemostasis. 78 (1): 392–5. doi:10.1055/s-0038-1657558. PMID   9198185.
  9. Khan KA, McMurray JL, Mohammed FM, Bicknell R (2019). "C-type lectin domain group 14 proteins in vascular biology, cancer and inflammation". FEBS Journal. 286 (17): 3299–3332. doi:10.1111/febs.14985. PMC   6852297 . PMID   31287944.CS1 maint: multiple names: authors list (link)
  10. 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. 165 (11): 6037–46. doi: 10.4049/jimmunol.165.11.6037 . PMID   11086035.
  11. 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.
  12. 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.
  13. 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