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's dependency on other cofactors, it is seen as a template mechanism. The activated | 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's 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, then the PZ dissociates with the ZPI to be used again. The activated FXa, N-termially bond to phospholipids, has an autolysis loop made up of acidic residues that binds with the ZPI's oppositely charged top region while the PZ's C-terminal binds with ZPI's helix G, more specifically with Tyr240 and Asp 293. | ||
