Sandbox Reserved 596: Difference between revisions
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'''PZ''' | '''PZ''' | ||
''Figure 1'' | |||
[[Image:Figure 1.JPG]] | [[Image:Figure 1.JPG]] | ||
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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 by interacting with the serine protease thrombin 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 human 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 the serpin protein Z-dependent protease inhibitor (ZPI). The PZ binds to ZPI and then carries the serpin to associate with phospholipid membrane bound FXa (follows right side of Figure 2). [6] | The function of PZ was studied in 1991 by Hogg and Stenflo, who initially hypothesized PZ to amplify the coagulation cascade by interacting with the serine protease thrombin 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 human 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 the serpin protein Z-dependent protease inhibitor (ZPI). The PZ binds to ZPI and then carries the serpin to associate with phospholipid membrane bound FXa (follows right side of Figure 2). [6] | ||
''Figure 2'' | |||
[[Image:Figure_2.JPG]] | [[Image:Figure_2.JPG]] | ||
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ZPI, a single-chain glycoprotein made in the liver with 423 residues and a molecular weight of 72 kDa, was first isolated in human plasma in 1998. ZPI is coded for by the gene SERPINA10 at locus 14q32.13 and is 25-35% homologous in its amino acid sequence to the serpin family of protease inhibitors.[7] Structurally ZPI has a characteristic serpin fold with three main β-sheets and exposed reactive center loop (Figure 3[[http://www.proteopedia.org/wiki/index.php/Image:Figure_3.JPG]] | ZPI, a single-chain glycoprotein made in the liver with 423 residues and a molecular weight of 72 kDa, was first isolated in human plasma in 1998. ZPI is coded for by the gene SERPINA10 at locus 14q32.13 and is 25-35% homologous in its amino acid sequence to the serpin family of protease inhibitors.[7] Structurally ZPI has a characteristic serpin fold with three main β-sheets and exposed reactive center loop (Figure 3) [[http://www.proteopedia.org/wiki/index.php/Image:Figure_3.JPG]]. The ZPI binding site for PZ is centered around its helix G (hG) and helix A (hA) while PZ’s bind site for ZPI is centered around its SP anion-binding site near the C-terminal. ZPI also has an atypical hydrogen bond configuration at the shutter region with the Asn186 of usual serpins being replaced by an aspartate (D213) in ZPI. This causes a different pattern of hydrogen bonds and the resulting placement of the D213 into a hydrophobic area underneath ZPI’s β-sheet A. D213 can therefore only form 1 hydrogen bond, compared to other serpins like antitrypsin and PAI-1 that form 4 and 3 hydrogen bonds respectively. [4] | ||
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'''PZ-ZPI Complex FXa Inhibition''' | '''PZ-ZPI Complex FXa Inhibition''' | ||
Once PZ has successfully formed a complex with ZPI, it guides the ZPI to activated FXa bound to platelet membranes. The PZ docks itself to the phospholipid membrane through its Gla domain and forms stabilizing bonds with FXa’s similarly membrane-bound Gla domain. ZPI interacts with FXa’s autolysis loop (E36, E37, or E39) through its negatively charged area (E231, D233, D313) on its top area, which unusually has a positively charged area as well (K253, K260, K308, R310). [4] The resulting PZ-ZPI-FXa tertiary complex is calcium and phospholipid dependent, increasing the rate of ZPI inhibition of FXa by 1000x. After the formation of the calcium-dependent PZ-ZPI-FXa complex and inhibitory changes begin, the PZ dissociates into the bloodstream to be used again. ZPI’s inhibitory action involves being proteolytically cleaved at its C-terminus by FXa, reducing ZPI’s molecular weight from 72 kDa to 68 kDa. [7] | Once PZ has successfully formed a complex with ZPI, it guides the ZPI to activated FXa bound to platelet membranes. The PZ docks itself to the phospholipid membrane through its Gla domain and forms stabilizing bonds with FXa’s similarly membrane-bound Gla domain (Figure 4)[[Image:Figure 4.JPG]]. ZPI interacts with FXa’s autolysis loop (E36, E37, or E39) through its negatively charged area (E231, D233, D313) on its top area, which unusually has a positively charged area as well (K253, K260, K308, R310). [4] The resulting PZ-ZPI-FXa tertiary complex is calcium and phospholipid dependent, increasing the rate of ZPI inhibition of FXa by 1000x. After the formation of the calcium-dependent PZ-ZPI-FXa complex and inhibitory changes begin, the PZ dissociates into the bloodstream to be used again. ZPI’s inhibitory action involves being proteolytically cleaved at its C-terminus by FXa, reducing ZPI’s molecular weight from 72 kDa to 68 kDa. [7] | ||
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