This Sandbox is Reserved from January 10, 2010, through April 10, 2011 for use in BCMB 307-Proteins course taught by Andrea Gorrell at the University of Northern British Columbia, Prince George, BC, Canada.
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The role of thrombin and prothrombin in coagulation.
Thrombin is a trypsin-like serine protease which is best known for its role in blood clotting. In humans, the F2 gene codes for prothrombin, which is also known as Coagulation Factor II.[1][2] Clevage of prothrombin to form activated α-thrombin is a key step in the final common pathway of blood clotting, because clevage by thrombin activates several factors in blood clotting, especially fibrin, factor XIII, and protein C.[3]
Thrombin is comprised of two chains, often referred to as the and the . All known functional epitopes are found on the long chain. There is one active site, which in the case of 1ppb is occupied with .[4] Additionally, there are three structural disulfide bonds.
While thrombin is described as a trypsin-like serine protease, it is more specific than trypsin due to two exosites which bind the substrate at a point separate from the active site. These exosites also allow for more specific inhibition, since protein C and factor Xa have similar active sites but play very different roles in the clotting process.[3]
The serine protease catalytic triad in the active site of α-thrombin, bound to D-Phe-Pro-Arg chloromethylketone ligand.
RegulationRegulation
Prothrombin is proteolytically activated to α-thrombin by factor Xa. α-Thrombin is permanently inactivated by the Serine Protease Inhibitorantithrombin, with heparin as a cofactor, and allosterically regulated by sodium ion concentration. Thrombomodulin inhibits clevage of fibrinogen to fibrin, but also enhances α-thrombin activity with respect to protein C. Since activated protein C proteolytically inactivates earlier steps in the chain, this effectively reverses the role of thrombin from coagulant to anticoagulant.[3]
↑Bode W, Mayr I, Baumann U, Huber R, Stone SR, Hofsteenge J. The refined 1.9 A crystal structure of human alpha-thrombin: interaction with D-Phe-Pro-Arg chloromethylketone and significance of the Tyr-Pro-Pro-Trp insertion segment. EMBO J. 1989 Nov;8(11):3467-75. PMID:2583108
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