User:Cody Couperus/Sandbox 1: Difference between revisions

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==Introduction==

<scene name='58/583418/Thombin_main_secondary/2'>Thrombin</scene> is the serine protease that catalyzes the penultimate step in blood coagulation. It is activated from its zymogen, prothrombin, at the site of tissue injury by [[Factor_Xa | FXa]] and its cofactor FVa in the presence of phospholipid membrane and calcium. Thrombin is then able to catalyze the cleavage of [[Fibrinogen | fibrinogen]] to insoluable fibrin which spontaneously polymerizes to form a stable clot.<ref name="zero">PMID: 7023326</ref><ref name="one">PMID: 11001069</ref> Thrombin also acts as a procoagulant by:

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By balancing substrate specificity, activity, and inhibition thrombin plays a central role in the blood coagulation cascade. <ref name="three"/>

==Thrombin Life Cycle==

Upon tissue damage tissue factor (TF) is released by subendothelial cells. This interacts with circulating FVIIa, a zymogen-like serine protease, significantly increasing its activity. The FVIIa-TF complex activates FVII, FIX, and FX. The now active FXa cleaves prothrombin bound to membranes through its Gla domain, activating it to thrombin. ~~The later will interact~~ with platelet membrane protein GpIbα and subsequently cleave protease activated receptor-1 (PAR1) causing a signaling cascade which leads to platelet α-granule release and membrane flipping exposing the negatively charged phosphatidylserine. The platelet alpha granules contain the physiologically relevant pool of FVa. Thrombin also ~~leads to~~ activation of FIX, through FXI cleavage, and ~~FIII~~ which form the Xase complex to activate FX. FVa and FXa form the prothrombinase complex in the presence of calcium and phospholipid. It causes rapid activation of prothrombin to thrombin. This increase in thrombin allows sufficient fibrinogen to be cleaved to fibrin which is able to polymerize to form a stable blood clot. Further supporting coagulation, thrombin activates FXIII, a transglutaminase that crosslinks fibrin at lysine residues.

Upon tissue damage tissue factor (TF) is released by subendothelial cells. This interacts with circulating FVIIa, a zymogen-like serine protease, significantly increasing its activity. The FVIIa-TF complex activates FVII, FIX, and FX. The now active FXa cleaves prothrombin bound to membranes through its Gla domain, activating it to thrombin.

The structure of thrombin facilitates its inactivation. Once the endothelial lining is reached thrombin binds heparin glycosaminoglycans. This facilitates its inactivation by serpin inhibitors antithrombin and heparin cofactor II. In addition, thrombin will interact with thrombomodulin which significantly increases its catalytic efficiency activating protein C. Activated protein C inactivates FVIIa and FVa thus down regulating thrombin generation.

Thrombin interacts with platelet membrane protein GpIbα and subsequently cleave protease activated receptor-1 (PAR1) causing a signaling cascade which leads to platelet α-granule release and membrane flipping exposing the negatively charged phosphatidylserine. The platelet alpha granules contain the physiologically relevant pool of FVa.

Thrombin also causes activation of FIX, through FXI cleavage, and FVIII which form the Xase complex to activate FX. FVa and FXa form the prothrombinase complex in the presence of calcium and phospholipid. It causes rapid activation of prothrombin to thrombin. This increase in thrombin allows sufficient fibrinogen to be cleaved to fibrin which is able to polymerize to form a stable blood clot.

Further supporting coagulation, thrombin activates FXIII, a transglutaminase that crosslinks fibrin at lysine residues.

The structure of thrombin facilitates its inactivation.

Once the endothelial lining is reached thrombin binds heparin glycosaminoglycans. This facilitates its inactivation by serpin inhibitors antithrombin and heparin cofactor II. In addition, thrombin will interact with thrombomodulin which significantly increases its catalytic efficiency activating protein C. Activated protein C inactivates FVIIa and FVa thus down regulating thrombin generation.

Thrombin plays a critical dual role in blood coagulation. It must be both promiscuous and specific so that it may complete both procoagulant and anticoagulant functions. The structure of thrombin facilitates its important physiologic functions.

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+<StructureSection load='1PPB' size='350' side='right' caption='Thrombin (1PPB) viewed in cartoon representation colored by secondary structure. Active site residues Ser195, Asp102, and His57 are viewed in ball and stick form.' scene='58/583418/Thombin_main_secondary/2'>
 ==Introduction==
 <scene name='58/583418/Thombin_main_secondary/2'>Thrombin</scene> is the serine protease that catalyzes the penultimate step in blood coagulation. It is activated from its zymogen, prothrombin, at the site of tissue injury by [[Factor_Xa | FXa]] and its cofactor FVa in the presence of phospholipid membrane and calcium. Thrombin is then able to catalyze the cleavage of [[Fibrinogen | fibrinogen]] to insoluable fibrin which spontaneously polymerizes to form a stable clot.<ref name="zero">PMID: 7023326</ref><ref name="one">PMID: 11001069</ref> Thrombin also acts as a procoagulant by:
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 By balancing substrate specificity, activity, and inhibition thrombin plays a central role in the blood coagulation cascade. <ref name="three"/>
-<StructureSection load='1PPB' size='350' side='right' caption='Thrombin (1PPB) viewed in cartoon representation colored by secondary structure. Active site residues Ser195, Asp102, and His57 are viewed in ball and stick form.' scene='58/583418/Thombin_main_secondary/2'>
 ==Thrombin Life Cycle==
-Upon tissue damage tissue factor (TF) is released by subendothelial cells. This interacts with circulating FVIIa, a zymogen-like serine protease, significantly increasing its activity. The FVIIa-TF complex activates FVII, FIX, and FX. The now active FXa cleaves prothrombin bound to membranes through its Gla domain, activating it to thrombin. The later will interact with platelet membrane protein GpIbα and subsequently cleave protease activated receptor-1 (PAR1) causing a signaling cascade which leads to platelet α-granule release and membrane flipping exposing the negatively charged phosphatidylserine. The platelet alpha granules contain the physiologically relevant pool of FVa. Thrombin also leads to activation of FIX, through FXI cleavage, and FIII which form the Xase complex to activate FX. FVa and FXa form the prothrombinase complex in the presence of calcium and phospholipid. It causes rapid activation of prothrombin to thrombin. This increase in thrombin allows sufficient fibrinogen to be cleaved to fibrin which is able to polymerize to form a stable blood clot. Further supporting coagulation, thrombin activates FXIII, a transglutaminase that crosslinks fibrin at lysine residues.
+Upon tissue damage tissue factor (TF) is released by subendothelial cells. This interacts with circulating FVIIa, a zymogen-like serine protease, significantly increasing its activity. The FVIIa-TF complex activates FVII, FIX, and FX. The now active FXa cleaves prothrombin bound to membranes through its Gla domain, activating it to thrombin.
-The structure of thrombin facilitates its inactivation. Once the endothelial lining is reached thrombin binds heparin glycosaminoglycans. This facilitates its inactivation by serpin inhibitors antithrombin and heparin cofactor II. In addition, thrombin will interact with thrombomodulin which significantly increases its catalytic efficiency activating protein C. Activated protein C inactivates FVIIa and FVa thus down regulating thrombin generation.
+Thrombin interacts with platelet membrane protein GpIbα and subsequently cleave protease activated receptor-1 (PAR1) causing a signaling cascade which leads to platelet α-granule release and membrane flipping exposing the negatively charged phosphatidylserine. The platelet alpha granules contain the physiologically relevant pool of FVa.
+Thrombin also causes activation of FIX, through FXI cleavage, and FVIII which form the Xase complex to activate FX. FVa and FXa form the prothrombinase complex in the presence of calcium and phospholipid. It causes rapid activation of prothrombin to thrombin. This increase in thrombin allows sufficient fibrinogen to be cleaved to fibrin which is able to polymerize to form a stable blood clot.
+Further supporting coagulation, thrombin activates FXIII, a transglutaminase that crosslinks fibrin at lysine residues.
+The structure of thrombin facilitates its inactivation.
+Once the endothelial lining is reached thrombin binds heparin glycosaminoglycans. This facilitates its inactivation by serpin inhibitors antithrombin and heparin cofactor II. In addition, thrombin will interact with thrombomodulin which significantly increases its catalytic efficiency activating protein C. Activated protein C inactivates FVIIa and FVa thus down regulating thrombin generation.
 Thrombin plays a critical dual role in blood coagulation. It must be both promiscuous and specific so that it may complete both procoagulant and anticoagulant functions. The structure of thrombin facilitates its important physiologic functions.