Protein S (PS), a 75-kDa macromolecule, is a key negative regulator of blood coagulation. PS deficiency and dysfunction cause life-threatening thrombotic conditions, such as neonatal purpura fulminans deep vein thrombosis and stroke. PS has long been described as a cofactor for both activated Protein C (APC) and Tissue Factor Pathway Inhibitor (TFPI). However, literature have only an incomplete understanding of the precise anticoagulant function of PS. With the prior NIH funding, we localized the PS binding site to heparin-binding exosites (HBE) of FIXa. We found out that the FIXa Gla and EGF domains impart essential conformational stability of PS binding. We discovered a novel regulatory activity for PS, i.e., PS binds and directly inhibits coagulation Factor IXa (FIXa). This previously unknown activity of PS may largely explain its vital requirement in coagulation. We are trying to find out how PS interacts with and inhibits FIXa in vitro and in vivo.
The main goal of this project is to establish the explicit importance of the PS-FIXa interaction, exclusive of PS interactions with TFPI and APC.
Furthermore, a comprehensive understanding of the interaction between FIXa and PS will enable us in the long term to create a PS-based polypeptide (mimetic) that specifically inhibits FIXa and could treat thrombophilia caused by aberrant genetic upregulation of FIXa or by PS deficiency.