Zinc (II) selectively enhances the inhibition of coagulation factor XIa by protease nexin-2/amyloid beta-protein precursor.
Protease nexin-2 (PN-2) is the secreted isoform of the Alzheimer's Amyloid beta-Protein Precursor (A beta PP) that contains the Kunitz-type protease inhibitor (KPI) domain. PN-2/A beta PP is a potent inhibitor of coagulation factor XIa (FXIa) and is secreted in large quantities by activated platelets suggesting a normal function in regulating this protease at sites of vascular injury. In the present study, the effect of Zn2+ on the protease inhibitory properties of PN-2/A beta PP was quantitatively investigated. Zn2+ (1 microM to 1 mM) had no effect on the inhibition of trypsin or chymotrypsin by PN-2/A beta PP. In contrast, Zn2+ at concentrations > 1 microM increased the inhibition of FXIa by PN-2/A beta PP. Enhancement of FXIa inhibition was virtually saturated at approximately 100 microM Zn2+ resulting in a final Ki approximately 6.0 x 10(-11) M. Zn2+ had no effect on the inhibition of FXIa by a purified, recombinant KPI domain of PN-2/A beta PP indicating that the native protein is required for the potentiation of FXIa inhibition. Heparin and Zn2+ were found to further augment each other's ability to stimulate the inhibition of FXIa by PN-2/A beta PP. Together, these findings suggest that the interaction of Zn2+ with PN-2/A beta PP may be important for optimal inhibition of FXIa.
Van Nostrand
W E
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Department of Microbiology and Molecular Genetics College of Medicine, University of California, Irvine 92717-4025, USA.
D016564:Amyloid beta-Protein Precursor / Q000187:drug effects* / Q000494:pharmacology; D002352:Carrier Proteins / Q000187:drug effects* / Q000494:pharmacology; D002413:Cations, Divalent; D002478:Cells, Cultured; D015945:Factor XIa / Q000037:antagonists & inhibitors*; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D058255:Protease Nexins; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D015032:Zinc / Q000494:pharmacology*
C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D002352:Carrier Proteins; D002413:Cations, Divalent; D058255:Protease Nexins; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; D006493:Heparin; D015945:Factor XIa; D015032:Zinc