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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | PROZ, PZ, Protein Z, protein Z, vitamin K dependent plasma glycoprotein | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM:176895;MGI:1860488;HomoloGene:2890;GeneCards:PROZ;OMA:PROZ - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Protein Z (PZ orPROZ),vitamin K-dependent protein Z, is aprotein encoded in the human by thePROZgene.[6][7]
Protein Z is a member of thecoagulation cascade, the group of blood proteins that leads to the formation ofblood clots. It is aglycoprotein. Protein Z functions to inhibit blood coagulation by binding to an inhibitor.[8] It is aGLA domain protein and thusVitamin K-dependent, and its functionality is therefore impaired inwarfarin therapy.
Although it is not enzymatically active, it is structurally related to severalserine proteases of the coagulation cascade:Factors VII,IX,X andProtein C. Thecarboxyglutamate residues (which require Vitamin K) bind Protein Z tophospholipid surfaces.
The main role of Protein Z appears to be the degradation ofFactor Xa. This is done byProtein Z-related protease inhibitor (ZPI), but the reaction is accelerated 1000-fold by the presence of Protein Z. Oddly, ZPI also degradesFactor XI, but this reaction does not require the presence of Protein Z. ZPI activated by Protein Z does not appear to happen because of its conformation, but proximity to each other. When Protein Z in bound to ZPI, it will bind to the same phospholipid surface as Factor Xa. This is what promotes the inhibition of Factor Xa.[9]
In some studies, deficiency states have been associated with a propensity tothrombosis. Others, however, link it tobleeding tendency; there is no clear explanation for this, as it acts physiologically as an inhibitor, and deficiency would logically have led to a predisposition forthrombosis.
It is 62kDa large and 396amino acids long. ThePROZgene is located onchromosome 13 (13q34).
It has four domains: aGLA-rich region, two EGF-like domains and a trypsin-like domain. It lacks theserine residue that would make it catalytically active as aserine protease.
Protein Z was first isolated incattle blood by Christopher Prowse and Peter Esnouf in 1977,[10] and Broze & Miletich determined it in human plasma in 1984.[11] Protein Z found in humans was given the same name as the one found in cattle for a few reasons. When looking at these isolated proteins it was found that they both have similar molecular weight, a similar composition of amino acids, and a similar Amino Terminal sequences.[12] These similarities in molecular composition of the protein found in cattle and humans was great enough that it can be concluded they were the same protein. When Protein Z was first discovered, it was theorized to be a form of Factor X instead of its own individual protein. Research had to be done to isolate this protein to find out if it was a form of Factor X or not. To test this, Vitamin K dependents were removed from the sample by adsorption to barium citrate, then an ion exchange chromatography was performed. This process showed that there was no Factor X in the isolated protein. The purified Protein Z in this experiment was distinct from Factor X, proving it was a separate protein.[12]
Structural analysis of Protein Z will allow better understanding of its function. TheRamachandran plot for Protein Z indicates it will form alpha helices. The final structure, all alpha domain, was determined by x-ray diffraction. It consists of chain A and B, which are both helix-loop-helix motifs.PDB:1LP1[5] The secondary structures of this protein are color coded in the image in the top left; pink represents the strands, yellow represents alpha helices and white is the coils.
There are many reasons that Protein Z is important in health. In pregnancy it is vital that the protein is functioning correctly. It has been found that if it isn't functioning correctly, it can lead to fetal death or hypersensitive disorders in pregnancy. This happens because when the levels of this protein drop too low, it can lead to fetal growth restrictions.[13] Another possible effect is having a high sensitivity to this protein which could correlate with diabetes.[14] In women diagnosed with ovarian cancers, it was found the protein was inhibiting Factor Xa which happens because there is a lower regulation of this protein in cancer cells.[15]
