Thrombomodulin links coagulation to inflammation and immunity.

Abstract:

:Thrombomodulin (TM) is a type 1 membrane bound glycoprotein that has a C-type lectin domain at its Nterminus, 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.

journal_name

Curr Drug Targets

journal_title

Current drug targets

authors

Morser J

doi

10.2174/138945012799424606

subject

Has Abstract

pub_date

2012-03-01 00:00:00

pages

421-31

issue

3

eissn

1389-4501

issn

1873-5592

pii

BSP/CDT/E-Pub/00368

journal_volume

13

pub_type

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