thrombomodulin

In humans, thrombomodulin is encoded by the {{gene|THBD}} gene.{{cite journal | vauthors = Wen DZ, Dittman WA, Ye RD, Deaven LL, Majerus PW, Sadler JE | title = Human thrombomodulin: complete cDNA sequence and chromosome localization of the gene | journal = Biochemistry | volume = 26 | issue = 14 | pages = 4350–4357 | date = July 1987 | pmid = 2822087 | doi = 10.1021/bi00388a025 }} 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.{{cite journal | vauthors = Sadler JE | title = Thrombomodulin structure and function | journal = Thrombosis and Haemostasis | volume = 78 | issue = 1 | pages = 392–395 | date = July 1997 | pmid = 9198185 | doi = 10.1055/s-0038-1657558 | s2cid = 32297505 | authorlink1 = J. Evan Sadler }}

It is a member of the C-type lectin domain (CTLD) group 14 family.{{cite journal | vauthors = Khan KA, McMurray JL, Mohammed F, Bicknell R | title = C-type lectin domain group 14 proteins in vascular biology, cancer and inflammation | journal = The FEBS Journal | volume = 286 | issue = 17 | pages = 3299–3332 | date = September 2019 | pmid = 31287944 | pmc = 6852297 | doi = 10.1111/febs.14985 }}

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|date=February 2015}}

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).{{cite journal | vauthors = Delvaeye M, Noris M, De Vriese A, Esmon CT, Esmon NL, Ferrell G, Del-Favero J, Plaisance S, Claes B, Lambrechts D, Zoja C, Remuzzi G, Conway EM | display-authors = 6 | title = Thrombomodulin mutations in atypical hemolytic-uremic syndrome | journal = The New England Journal of Medicine | volume = 361 | issue = 4 | pages = 345–357 | date = July 2009 | pmid = 19625716 | pmc = 3530919 | doi = 10.1056/NEJMoa0810739 }}

The antigen described as BDCA-3{{cite journal | vauthors = Dzionek A, Fuchs A, Schmidt P, Cremer S, Zysk M, Miltenyi S, Buck DW, Schmitz J | display-authors = 6 | title = BDCA-2, BDCA-3, and BDCA-4: three markers for distinct subsets of dendritic cells in human peripheral blood | journal = Journal of Immunology | volume = 165 | issue = 11 | pages = 6037–6046 | date = December 2000 | pmid = 11086035 | doi = 10.4049/jimmunol.165.11.6037 | doi-access = free }} has turned out to be identical to thrombomodulin.{{cite journal | vauthors = Dzionek A, Inagaki Y, Okawa K, Nagafune J, Röck J, Sohma Y, Winkels G, Zysk M, Yamaguchi Y, Schmitz J | display-authors = 6 | title = Plasmacytoid dendritic cells: from specific surface markers to specific cellular functions | journal = Human Immunology | volume = 63 | issue = 12 | pages = 1133–1148 | date = December 2002 | pmid = 12480257 | doi = 10.1016/S0198-8859(02)00752-8 }} 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.{{citation needed|date=February 2015}}

Thrombomodulin has been shown to interact with thrombin.{{cite journal | vauthors = Bajzar L, Morser J, Nesheim M | title = TAFI, or plasma procarboxypeptidase B, couples the coagulation and fibrinolytic cascades through the thrombin-thrombomodulin complex | journal = The Journal of Biological Chemistry | volume = 271 | issue = 28 | pages = 16603–16608 | date = July 1996 | pmid = 8663147 | doi = 10.1074/jbc.271.28.16603 | doi-access = free }}{{cite journal | vauthors = Jakubowski HV, Owen WG | title = Macromolecular specificity determinants on thrombin for fibrinogen and thrombomodulin | journal = The Journal of Biological Chemistry | volume = 264 | issue = 19 | pages = 11117–11121 | date = July 1989 | pmid = 2544585 | doi = 10.1016/S0021-9258(18)60437-5 | doi-access = free }}

{{Reflist}}

{{refbegin | 2}}

• {{cite journal | vauthors = Esmon CT | title = Thrombomodulin as a model of molecular mechanisms that modulate protease specificity and function at the vessel surface | journal = FASEB Journal | volume = 9 | issue = 10 | pages = 946–955 | date = July 1995 | pmid = 7615164 | doi = 10.1096/fasebj.9.10.7615164 | doi-access = free | s2cid = 19565674 }}
• {{cite journal | vauthors = Ohlin AK, Norlund L, Marlar RA | title = Thrombomodulin gene variations and thromboembolic disease | journal = Thrombosis and Haemostasis | volume = 78 | issue = 1 | pages = 396–400 | date = July 1997 | pmid = 9198186 | doi = 10.1055/s-0038-1657559 | s2cid = 25122238 }}
• {{cite journal | vauthors = Van de Wouwer M, Collen D, Conway EM | title = Thrombomodulin-protein C-EPCR system: integrated to regulate coagulation and inflammation | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 24 | issue = 8 | pages = 1374–1383 | date = August 2004 | pmid = 15178554 | doi = 10.1161/01.ATV.0000134298.25489.92 | doi-access = }}
• {{cite journal | vauthors = Boffa MC, Jackman RW, Peyri N, Boffa JF, George B | title = Thrombomodulin in the central nervous system | journal = Nouvelle Revue Française d'Hématologie | volume = 33 | issue = 6 | pages = 423–429 | year = 1991 | pmid = 1667949 }}
• {{cite journal | vauthors = Jackman RW, Beeler DL, Fritze L, Soff G, Rosenberg RD | title = Human thrombomodulin gene is intron depleted: nucleic acid sequences of the cDNA and gene predict protein structure and suggest sites of regulatory control | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 84 | issue = 18 | pages = 6425–6429 | date = September 1987 | pmid = 2819876 | pmc = 299089 | doi = 10.1073/pnas.84.18.6425 | doi-access = free | bibcode = 1987PNAS...84.6425J }}
• {{cite journal | vauthors = Suzuki K, Kusumoto H, Deyashiki Y, Nishioka J, Maruyama I, Zushi M, Kawahara S, Honda G, Yamamoto S, Horiguchi S | display-authors = 6 | title = Structure and expression of human thrombomodulin, a thrombin receptor on endothelium acting as a cofactor for protein C activation | journal = The EMBO Journal | volume = 6 | issue = 7 | pages = 1891–1897 | date = July 1987 | pmid = 2820710 | pmc = 553573 | doi = 10.1002/j.1460-2075.1987.tb02448.x }}
• {{cite journal | vauthors = Wen DZ, Dittman WA, Ye RD, Deaven LL, Majerus PW, Sadler JE | title = Human thrombomodulin: complete cDNA sequence and chromosome localization of the gene | journal = Biochemistry | volume = 26 | issue = 14 | pages = 4350–4357 | date = July 1987 | pmid = 2822087 | doi = 10.1021/bi00388a025 }}
• {{cite journal | vauthors = Shirai T, Shiojiri S, Ito H, Yamamoto S, Kusumoto H, Deyashiki Y, Maruyama I, Suzuki K | display-authors = 6 | title = Gene structure of human thrombomodulin, a cofactor for thrombin-catalyzed activation of protein C | journal = Journal of Biochemistry | volume = 103 | issue = 2 | pages = 281–285 | date = February 1988 | pmid = 2836377 | doi = 10.1093/oxfordjournals.jbchem.a122261 | citeseerx = 10.1.1.1006.6759 }}
• {{cite journal | vauthors = Yonezawa S, Maruyama I, Tanaka S, Nakamura T, Sato E | title = 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 | journal = Cancer | volume = 62 | issue = 3 | pages = 569–576 | date = August 1988 | pmid = 2839283 | doi = 10.1002/1097-0142(19880801)62:3<569::AID-CNCR2820620322>3.0.CO;2-T | s2cid = 28744944 | doi-access = }}
• {{cite journal | vauthors = Ishii H, Majerus PW | title = Thrombomodulin is present in human plasma and urine | journal = The Journal of Clinical Investigation | volume = 76 | issue = 6 | pages = 2178–2181 | date = December 1985 | pmid = 3001144 | pmc = 424339 | doi = 10.1172/JCI112225 }}
• {{cite journal | vauthors = Adler M, Seto MH, Nitecki DE, Lin JH, Light DR, Morser J | title = The structure of a 19-residue fragment from the C-loop of the fourth epidermal growth factor-like domain of thrombomodulin | journal = The Journal of Biological Chemistry | volume = 270 | issue = 40 | pages = 23366–23372 | date = October 1995 | pmid = 7559494 | doi = 10.1074/jbc.270.40.23366 | doi-access = free }}
• {{cite journal | vauthors = Ohlin AK, Marlar RA | title = The first mutation identified in the thrombomodulin gene in a 45-year-old man presenting with thromboembolic disease | journal = Blood | volume = 85 | issue = 2 | pages = 330–336 | date = January 1995 | pmid = 7811989 | doi = 10.1182/blood.V85.2.330.330 | doi-access = free }}
• {{cite journal | vauthors = Srinivasan J, Hu S, Hrabal R, Zhu Y, Komives EA, Ni F | title = Thrombin-bound structure of an EGF subdomain from human thrombomodulin determined by transferred nuclear Overhauser effects | journal = Biochemistry | volume = 33 | issue = 46 | pages = 13553–13560 | date = November 1994 | pmid = 7947766 | doi = 10.1021/bi00250a007 }}
• {{cite journal | vauthors = Gerlitz B, Hassell T, Vlahos CJ, Parkinson JF, Bang NU, Grinnell BW | title = Identification of the predominant glycosaminoglycan-attachment site in soluble recombinant human thrombomodulin: potential regulation of functionality by glycosyltransferase competition for serine474 | journal = The Biochemical Journal | volume = 295 | issue = 1 | pages = 131–140 | date = October 1993 | pmid = 8216207 | pmc = 1134829 | doi = 10.1042/bj2950131 }}
• {{cite journal | vauthors = Yasuda K, Espinosa R, Davis EM, Le Beau MM, Bell GI | title = Human somatostatin receptor genes: localization of SSTR5 to human chromosome 20p11.2 | journal = Genomics | volume = 17 | issue = 3 | pages = 785–786 | date = September 1993 | pmid = 8244401 | doi = 10.1006/geno.1993.1410 }}
• {{cite journal | vauthors = Yamamoto S, Mizoguchi T, Tamaki T, Ohkuchi M, Kimura S, Aoki N | title = Urinary thrombomodulin, its isolation and characterization | journal = Journal of Biochemistry | volume = 113 | issue = 4 | pages = 433–440 | date = April 1993 | pmid = 8390446 | doi = 10.1093/oxfordjournals.jbchem.a124063 }}
• {{cite journal | vauthors = Meininger DP, Hunter MJ, Komives EA | title = Synthesis, activity, and preliminary structure of the fourth EGF-like domain of thrombomodulin | journal = Protein Science | volume = 4 | issue = 9 | pages = 1683–1695 | date = September 1995 | pmid = 8528067 | pmc = 2143218 | doi = 10.1002/pro.5560040904 }}
• {{cite journal | vauthors = Maglott DR, Feldblyum TV, Durkin AS, Nierman WC | title = Radiation hybrid mapping of SNAP, PCSK2, and THBD (human chromosome 20p) | journal = Mammalian Genome | volume = 7 | issue = 5 | pages = 400–401 | date = May 1996 | pmid = 8661740 | doi = 10.1007/s003359900120 | s2cid = 34951074 | author-link1 = Donna R. Maglott }}

{{refend}}

• [https://www.ncbi.nlm.nih.gov/books/NBK1367/ GeneReviews/NCBI/NIH/UW entry on Atypical Hemolytic-Uremic Syndrome]
• [https://www.ncbi.nlm.nih.gov/omim/277400,120700,120920,134370,134371,138470,188040,217030,235400,605336,605337,612922,612923,612924,612925,612926,120700,120920,134370,134371,138470,188040,217030,235400,605336,605337,612922,612923,612924,612925,612926 OMIM entries on Atypical Hemolytic-Uremic Syndrome]

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{{Clusters of differentiation}}

Category:Coagulation system

Category:Clusters of differentiation