Phosphatidylserine and Phosphatidylethanolamine Regulate the Structure and Function of FVIIaand Its Interaction with Soluble Tissue Factor

Tanusree Sengupta, Tilen Koklic, Barry R Lentz, Rinku Majumder
Bioscience Reports 2021 January 22
Cell membranes have important functions in many steps of the blood coagulation cascade, including the activation of factor X (FX) by the factor VIIa (FVIIa)-tissue factor (TF) complex (extrinsic Xase). FVIIa shares structural similarity with factor IXa (FIXa) and FXa. FIXa and FXa are regulated by binding to phosphatidylserine (PS)-containing membranes via their γ-carboxy-glutamic acid (Gla) and epidermal growth-factor (EGF) domains.  Although FVIIa also has a Gla-rich region, its affinity for PS-containing membranes is much lower compared to that of FIXa and FXa. Research suggests that a more common endothelial cell lipid, phosphatidylethanolamine (PE), might augment the contribution of PS in FVIIa membrane-binding and proteolytic activity. We used soluble forms of PS and PE (C6PS, C6PE) to test the hypothesis that the two lipids bind to FVIIa jointly to promote FVIIa membrane binding and proteolytic activity.  By equilibrium dialysis and tryptophan fluorescence, we found two sites on FVIIa that bound equally to C6PE and C6PS with Kd of ~ 150 -160 μM, however, deletion of Gla domain reduced the binding affinity. Binding of lipids occurred with greater affinity (Kd ~ 70-80 μM) when monitored by FVIIa proteolytic activity. Global fitting of all data sets indicated independent binding of two molecules of each lipid. The proteolytic activity of FVIIa increased by ~50-100-fold in the presence of soluble Tissue Factor (sTF) plus C6PS/C6PE.  However, the proteolytic activity of Gla-deleted FVIIa in the presence of sTF was reduced drastically, suggesting the importance of Gla domain to maintain full proteolytic activity.

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