Enhanced rate of cleavage at Arg-306 and Arg-506 in coagulation factor Va by Gla domain-mutated human-activated protein C.

The Journal of Biological Chemistry
Yong-Hui SunBjörn Dahlbäck

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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Citations

May 27, 2008·The Journal of Biological Chemistry·Mårten SteenBjörn Dahlbäck
Apr 26, 2013·Thrombosis and Haemostasis·Sara CalzavariniBjörn Dahlbäck
Aug 28, 2013·The Journal of Clinical Investigation·Lisa M VincentBjörn Dahlbäck
Oct 30, 2008·Thrombosis Journal·Karl MalmBjörn Dahlbäck
Aug 10, 2011·Hämostaseologie·H Weiler
Nov 11, 2011·Thrombosis and Haemostasis·Karin C A A WildhagenGerry A F Nicolaes
Oct 31, 2009·Journal of Thrombosis and Haemostasis : JTH·S Tran, B Dahlbäck
Aug 29, 2006·The Journal of Biological Chemistry·Eva A NorstrømBjörn Dahlbäck
Jan 17, 2008·The Journal of Biological Chemistry·Sinh TranBjörn Dahlbäck

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