Sandbox Reserved 596: Difference between revisions
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The function of PZ was studied in 1991 by Hogg and Stenflo, who initially hypothesized PZ to amplify the coagulation cascade but found that bovine PZ has a higher affinity for thrombin than human PZ due to a 36 amino acid addition to the bovine PZ's C-terminus. Furthermore, they found that PZ virtually had no involvement in binding thrombin to phospholipids. It was not until 1998 that Han et al. described PZ present in the body as a complex with protein Z-dependent protease inhibitor (ZPI). The ZPI and PZ complex acts as an inhibitor of factor Xa (FXa), an important enzyme in prothrombin activation, attached to platelets and other phopholipid surfaces (forming a calcium-dependent teritary complex). FXa is inhibited by two serine protease inhibitors, or serpins, antithrombin and ZPI with their cofactors heparin and PZ respectively. PZ binds to the serpin ZPI on the opposite side as where the allosterically activating heparin binds to the serpin antithrombin. When analyzing the antithrombin-FXa Michaelis complex, it is conclusive that FXa can bind to ZPI in a similarly configured complex. | The function of PZ was studied in 1991 by Hogg and Stenflo, who initially hypothesized PZ to amplify the coagulation cascade but found that bovine PZ has a higher affinity for thrombin than human PZ due to a 36 amino acid addition to the bovine PZ's C-terminus. Furthermore, they found that PZ virtually had no involvement in binding thrombin to phospholipids. It was not until 1998 that Han et al. described PZ present in the body as a complex with protein Z-dependent protease inhibitor (ZPI). The ZPI and PZ complex acts as an inhibitor of factor Xa (FXa), an important enzyme in prothrombin activation, attached to platelets and other phopholipid surfaces (forming a calcium-dependent teritary complex). FXa is inhibited by two serine protease inhibitors, or serpins, antithrombin and ZPI with their cofactors heparin and PZ respectively. PZ binds to the serpin ZPI on the opposite side as where the allosterically activating heparin binds to the serpin antithrombin. When analyzing the antithrombin-FXa Michaelis complex, it is conclusive that FXa can bind to ZPI in a similarly configured complex. | ||
It has been shown that PZ and ZPI travel the body in plasma already bonded together as a complex and later binds to activated FXa bound to the phospholipid membrane. PZ has a high affinity for ZPI and speeds up its interaction FXa by 1000x with calcium and phospholipids present. While ZPI requires the presence of PZ, calcium, and phospholipids to inhibit FXa, ZPI does not need other components to inhibit another coagulation factor, factor XI. Because this tertiary complex | It has been shown that PZ and ZPI travel the body in plasma already bonded together as a complex and later binds to activated FXa bound to the phospholipid membrane. PZ has a high affinity for ZPI and speeds up its interaction FXa by 1000x with calcium and phospholipids present. While ZPI requires the presence of PZ, calcium, and phospholipids to inhibit FXa, ZPI does not need other components to inhibit another coagulation factor, factor XI. Because this tertiary complex of PZ, ZPI, and FXa has dependency on other cofactors, it is seen as a template mechanism. The PZ catalytically stimulates interaction of ZPI and FXa by associating into the tertiary complex, formed by PZ's C-terminal bonding with ZPI's helix G, more specifically with Tyr240 and Asp 293 and ZPI's oppositely charged top region bound to the FXa's autolysis loop made up of acidic residues. Once the inhibitory complex is formed with the necessary cofactors present, the PZ dissociates to be used again. | ||
'''Clinical Relevance''' | '''Clinical Relevance''' | ||
'''References''' | '''References''' | ||
