Pregnancy zone protein-tissue-type plasminogen activator complexes bind to low-density lipoprotein receptor-related protein (LRP).
Tissue-type plasminogen activator (t-PA), is a serine proteinase that catalyzes the initial and rate-limiting step in the fibrinolytic cascade. Its plasma activity is determined by the rate of release into the bloodstream, the rate of inhibition by plasminogen-activator inhibitor type 1 (PAI-1) and the rate of hepatic clearance. Two receptor systems contribute to the clearance of t-PA: the mannose receptor and the low-density lipoprotein receptor-related protein (LRP) that removes free t-PA as well as t-PA-PAI-1 complexes from the blood. During pregnancy a significant rise in the plasma levels of pregnancy zone protein (PZP) is observed, while alpha(2)-macroglobulin (alpha(2)-M) remains constant. Interestingly, the fibrinolytic activity is decreased during this period. In this context, we have recently demonstrated the in vitro formation of PZP-t-PA complexes. Here, we purified LRP from human placenta by affinity chromatography and then analyzed the binding specificity and affinity of PZP-proteinase complexes to the receptor by enzyme immunoassay (EIA). Our results clearly established that the binding of PZP-t-PA complexes to LRP was specific, saturable, and with K(d) = 337 +/- 31 nM. Moreover, by using the same EIA, we further observed that this binding was inhibited by receptor-associated protein. These data suggest that PZP, by binding to t-PA and promoting its clearance via LRP, might contribute in vivo to the downregulation of the fibrinolytic activity during pregnancy.
Sánchez
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MC
Departamento de Bioquímica Clínica, Universidad Nacional de Córdoba, 5000 Córdoba, Argentina. csanchez@bioclin.fcq.unc.edu.ar
Chiabrando
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GA
Vides
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MA
D005260:Female; D005342:Fibrinolysis; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D046911:Macromolecular Substances; D010920:Placenta / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000378:metabolism*; D011485:Protein Binding; D011971:Receptors, Immunologic / Q000378:metabolism*; D010959:Tissue Plasminogen Activator / Q000378:metabolism*
D026503:Low Density Lipoprotein Receptor-Related Protein-1; D046911:Macromolecular Substances; D017395:Plasminogen Activator Inhibitor 1; D011257:Pregnancy Proteins; D011971:Receptors, Immunologic; D010959:Tissue Plasminogen Activator