Sandbox Reserved 596: Difference between revisions
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== Protein Z == | == '''Protein Z''' == | ||
---- | ---- | ||
== '''Background''' == | |||
The human body maintains the many aspects of homeostasis, or biological equilibrium, through multiple physiological pathways. Hemostatic mechanisms have evolved over 400 million years to protect against the ever-present danger of fatal hemorrhage. [1] When inflicted by a wound resulting in internal or external bleeding, one of the two converging coagulation cascade branches is triggered to maintain hemostasis. If the wound is just an epithelial surface wound, the body reacts with the intrinsic pathway but if the wound is more traumatic, resulting in more extensive vascular and tissue damage, the extrinsic branch is used. This coagulation pathway is known as a cascade because the product of the previous reaction acts as an enzyme for the following reaction, a flow that can be attributed to the specificity of each enzyme along with positive and negative feedback loops to further control the directionality. [2] | The human body maintains the many aspects of homeostasis, or biological equilibrium, through multiple physiological pathways. Hemostatic mechanisms have evolved over 400 million years to protect against the ever-present danger of fatal hemorrhage. [1] When inflicted by a wound resulting in internal or external bleeding, one of the two converging coagulation cascade branches is triggered to maintain hemostasis. If the wound is just an epithelial surface wound, the body reacts with the intrinsic pathway but if the wound is more traumatic, resulting in more extensive vascular and tissue damage, the extrinsic branch is used. This coagulation pathway is known as a cascade because the product of the previous reaction acts as an enzyme for the following reaction, a flow that can be attributed to the specificity of each enzyme along with positive and negative feedback loops to further control the directionality. [2] | ||
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'''PZ''' | == '''PZ''' == | ||
''Figure 1'' | ''Figure 1'' | ||
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[[Image:Figure_2.JPG]] | [[Image:Figure_2.JPG]] | ||
== '''ZPI''' == | |||
<Structure load='3F1S' size='500' frame='true' align='right' caption='Protein Z (green) and Protein Z Dependent Inhibitor (blue) Complex' scene='Insert optional scene name here' /> | <Structure load='3F1S' size='500' frame='true' align='right' caption='Protein Z (green) and Protein Z Dependent Inhibitor (blue) Complex' scene='Insert optional scene name here' /> | ||
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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 (Figure 4). | 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). | ||
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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] | 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] | ||
== '''Clinical Relevence''' == | |||
Although PZ is conserved across many different species [5], the complete pathophysiological importance of PZ is still not completely known because many any clinical studies have resulted in conflicting conclusions. In 2001 Rice et al. wished to study just four important polymorphisms of the PROZ gene possibly linked to venous thrombosis but ultimately found and studied that PZ has 14 unique polymorphisms possible due to specific mutations. | |||
Lichy et al. studied specific the affects of mutations of Fg79a and promoter A-13g on cerebral ischema. | Lichy et al. studied specific the affects of mutations of Fg79a and promoter A-13g on cerebral ischema. | ||
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'''References''' | == '''References''' == | ||
[1] Corral, Javier et al. Protein Z/Z-dependent Protease Inhibitor (PZ/ZPI) Anticoagulant System and Thrombosis. British Journal of Haematology. 2007. 137(2): 99-108. | [1] Corral, Javier et al. Protein Z/Z-dependent Protease Inhibitor (PZ/ZPI) Anticoagulant System and Thrombosis. British Journal of Haematology. 2007. 137(2): 99-108. | ||
