Abstract
A Gla domain-mutated protein C variant, QGNSEDY, modified at positions 10-12, 23, 32-33, and 44, having enhanced affinity for negatively charged phospholipid and increased anticoagulant potential, was used to elucidate the importance of the interaction between the Gla domain and the phospholipid for the ability of activated protein C (APC) to inactivate factor Va (FVa). FVa degradation by wild type (WT)-APC and QGNSEDY-APC yielded similar fragments on Western blotting; QGNSEDY-APC was, however, considerably more efficient. The kinetic parameters for individual APC-mediated cleavages in FVa, i.e. at Arg-306 and Arg-506, were investigated at high and low phospholipid concentrations in the presence and absence of protein S. FVa variants 306Q679Q and 506Q679Q, which can only be cleaved at Arg-506 and Arg-306, respectively, were used. In the absence of protein S, QGNSEDY-APC was 17.8- and 4-fold more efficient than WT-APC in cleaving at Arg-306 and Arg-506, respectively, at high phospholipid. Similar values were obtained at low phospholipid. In the presence of protein S, QGNSEDYAPC was 6.8- and 3.2-fold more active than WT-APC in cleaving at Arg-306 and Arg-506, respectively, at high phospholipid. At low phospholipid, the correspond...Continue Reading
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