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 Amy loid beta-Protein Precursor (A beta PP) that contains the Kunitz-type protease inhibitor (KPl) domain. PN-2/A beta PP is a potent inhibitor of coagulation factor Xla (FXla) and is secreted in large quantities b y 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 q uantitatively investigated. Zn2+ (1 mu M 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 mu M increased the inhibition of FXla by PN -2/A beta PP. Enhancement of FXla inhibition was virtually saturated a t approximate to 100 mu M Zn2+ resulting in a final K-i approximate to 6.0 x 10(-11) M. Zn2+ had no effect on the inhibition of FXla by a pu rified, recombinant KPI domain of PN-2/A beta PP indicating that the n ative protein is required for the potentiation of FXla inhibition. Hep arin and Zn2+ were found to further augment each other's ability to st imulate the inhibition of FXla by PN2/A beta PP. Together, these findi ngs suggest that the interaction of Zn2+ with PN-2/A beta PP may be im portant for optimal inhibition of FXla.