Pregnancy zone protein

The first publication reporting PZP was produced in 1959 by O. Smithies. This was a result of an experimental process using starch gel zone-electrophoresis, which detected a protein band in the sera of 10% of the studied women in late pregnancy and after delivery. Nomenclature Since its discovery, PZP has been synonymously referred to by numerous names in scholarly literature. These include the following: α2-pregnoglobulin, pregnancy-associated α2-glycoprotein, α-acute-phase glycoprotein, alpha-2-macroglobulin like, Xh-antigen, Schwangerschaftsprotein-3, Pα-1, pregnancy-associated α-macroglobulin, pregnancy-associated globulin, and α2-PAG. == Gene expression and protein localisation ==

The PZP gene contains 36 exons and is located on the short arm of chromosome 12 at position 12-13. A number of tissues, such as the uterus, liver, and brain, have PZP expressed in them. The presence of PZP has been detected in blood plasma, cerebral spinal fluid, and synovial fluid. The amount of PZP in the plasma of healthy people in normal conditions has been identified as <0.03 mg/mL while for pregnant women this can rise to be at concentrations of 0.5 - 3.0 mg/mL. A 1976 study observing the roles of contraceptives on PZP amounts, resulted in speculation that estrogen plays some role in controlling PZP expression. The clone EPZP6 isolated from a human genomic library, has been observed to be a genomic clone of PZP. == Protein structure ==

Pregnancy zone proteins (PZPs) exist in the functionally active form as homodimers of 360 kDa molecular weights. This dimerisation of the constituent 180 kDa monomers happens by means of disulfide bridge bonds. PZPs are secreted in highly glycosylated form. The structure has been confirmed experimentally when denaturation of PZP demonstrated the 360 kDa entity, while subsequent reduction - subunits of 180 kDa. Of the latter, some were shown to be partially fragmented to 90 kDa as a result of cleavage. On each PZP subunit there is a thiol-ester group, a signal domain, a bait region and a receptor binding domain. A 1988 study of PZPs and three of its derivatives using monoclonal antibodies, showed that there is a possibility of a minimum of three various conformational states for PZP and its derivatives. In another study, experimentally, the hydrophobic surfaces displayed by α2M and PZP have been used to note that the conformational states of these two proteins display significant differences. == Biological activity and functions ==

Over many years PZP has been classified as a protease inhibitor, however, as was observed in a paper in 2016, more recently, the suggestion of the roles of a T-helper cell modulator and/or an extracellular chaperone has been made. In a wider context, however, the specific biological significance of PZP is yet to be determined. A suggested mechanism for the immunoregulatory function of PZP includes the proposal that PZP noncovalently sequesters ligands like IL-6.72, IL-2 and tumor necrosis factor-α. Amy R. Wyatt et al. observe that there is no substantial evidence to support suggestions of PZP being involved in the control intracellular protease activities including those of chymotrypsin-like enzymes. Due to faster interactions displayed between PZP with tissue-type plasminogen activator (tPA) than those of α2M and tPA, it has been proposed that since tPA is the major serine proteinase in the plasma fibrinolytic system, it may in fact be PZP that plays a role in controlling fibrinolytically-derived proteinases during pregnancy. Binding observations The macromolecules which the PZP has been shown to bind include those associated with pregnancy, such as the placenta growth factor, glycodelin, and the vascular endothelial growth factor. It has been stated that more compact, transformed conformations of PZP occur as a result of thioester bond cleavage of the PZP resulting from interaction with small amine molecules or proteases. The mechanisms of how these transformed PZPs, complexed with proteases, act as ligands for LRP are still enigmatic. It has been demonstrated that PZP has plasmin-binding capabilities. == Comparison with alpha-2-macroglobulin ==

α2M and PZP have been shown to have a similar primary structure. This has led to suggestions that the two proteins are evolutionarily related. == Links to diseases and health conditions ==

Observations have been made of PZP being associated with various diseases and conditions. Links of heightened PZP levels to later onset of Alzheimer's disease (AD) have been observed, with the PZP potentially originating in the brain. Furthermore, in postmortem examinations, the immunoreactivity of PZP in the cortex of AD patients was specifically seen in the microglial cells associated with senile plaques, and in some neurons. While PZP has been shown to be non-specific enough for use in HIV-1 diagnosis, it has been suggested as having potential value as a marker of prognosis if changes in PZP levels over time in HIV-1 patients are found to correspond to response to therapy and disease course. A study using mice serum to observe the role of proteins including PZP in identification of inflammatory bowel disease deduced that PZP may be used as one of a panel of six proteins proposed as a combined biomarker signature. PZP levels were found to not differ significantly in breast cancer patients, thus deeming this protein ineligible as a biomarker of this disease. PZP expression in relation to in-vitro fertilisation (IVF) has also been studied, showing upregulation. PZP was shown to be one the proteins determined as potential biomarkers of Poor Ovarian Responder (POR) in IVF. Low PZP concentrations have also been linked to miscarriage during the early stages of pregnancy. ==Modulation by estrogens==

The hepatic synthesis of PZP is modulated by estrogens, and PZP is by far the most estrogen-sensitive hepatic protein known. High doses of oral estrogens increase PZP levels by 20- to 30-fold, whereas sex hormone-binding globulin (SHBG) levels are increased only by 5- to 10-fold. Pregnancy, during which time estradiol levels strongly increase, is associated with 50- to 100-fold increased PZP levels. Besides estrogens, selective estrogen receptor modulators (SERMs) like tamoxifen increase PZP levels. The synthetic estrogen ethinylestradiol (EE) shows strongly disproportionate effect on PZP and SHBG levels compared to natural estradiol. Whereas 2 mg/day oral estradiol valerate increased PZP levels by 34%, 10 μg/day and 30 μg/day oral EE increased PZP by 496% and 790%, respectively. In a study of high-dose polyestradiol phosphate (160 mg/4 weeks) by intramuscular injection, with resulting estradiol levels of about 400 pg/mL, PZP levels did not meaningfully change. These findings indicate that both type of estrogen and route of administration modify the influence of estrogens on liver protein synthesis as well as associated estrogenic effects. ==References==