期刊
CURRENT DRUG TARGETS
卷 13, 期 3, 页码 421-431出版社
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/138945012799424606
关键词
Dendritic cells; protein C; thrombin; thrombin activatable fibrinolysis inhibitor (TAFI)
资金
- NHLBI NIH HHS [R01 HL057530] Funding Source: Medline
Thrombomodulin (TM) is a type 1 membrane bound glycoprotein that has a C-type lectin domain at its N-terminus, 6 copies of the epidermal growth factor-like (EGF) motif and serine/threonine rich domain carrying a glycosoaminoglycan external to the membrane. TM binds thrombin changing thrombin's substrate specificity from procoagulant and pro-inflammatory to anti-coagulant and anti-inflammatory because of the activation of protein C (PC) and thrombin-activatable fibrinolysis inhibitor (TAFI). Thrombin's anion binding site 1 binds to TM's EGF domains 5 and 6. EGF4 is required for PC activation and EGF3 and 4 for TAFI activation in addition to EGF56. The X-ray structure of thrombin bound to TM has been solved and shows few major alterations in the active site of thrombin. The lectin domain can bind high mobility group box protein 1 (HMGB1) and a sugar, Lewis(y). TM's lectin domain behaves as an antagonist to HMGB1 endowing it with intrinsic anti-inflammatory activity. Treatment of dendritic cells with TM converts them from immunogenic to tolerogenic. TM is necessary for maintenance of pregnancy as well as prevention of coagulation throughout life. Soluble TM has been developed as an anticoagulant possessing favorable pharmacokinetics that has been approved for treatment of disseminated intravascular coagulation in Japan.
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