Thursday, January 2, 2025
1/2/2025
Protein S (PS), a plasma anticoagulant, is vital for the maintenance of hemostasis. Deficiencies or abnormalities in PS can lead to thrombotic conditions such as pulmonary embolism, deep vein thrombosis, and acute small blood vessel coagulation. PS is a non- enzymatic cofactor for Activated Protein C and for Tissue Factor Pathway Inhibitor. Recently, we discovered that PS inhibits procoagulant FIXa. This significant finding likely explains the thrombotic pathology associated with PS deficiency. Thus, we seek to derive a complete understanding of the interaction between FIXa and PS and to establish the explicit importance of the PS-FIXa interaction, exclusive of PS interactions with APC and TFPI. Identification of the biochemical details of PS-FIXa interaction will enable development a small derivative of PS that could treat individuals who have excess FIXa activity (and excess blood clotting) and PS deficiencies or abnormalities. We have pinpointed the PS binding site to FIXa’s heparin-binding site and identified HBE residues necessary for PS-FIXa binding. We have established that the Gla and EGF domains of FIXa contribute to the stability of the interaction with PS, and we discovered that the isolated Laminin G1+2 domains of PS are effective inhibitors of FIXa. For this project, we will use the following in vivo and in vitro approaches to achieve a thorough understanding of the interaction of PS with FIXa: (1) Confirm PS domains required for FIXa inhibition, (2) Identify PS residues required for FIXa inhibition, and (3) Define the in vivo interaction of FIXa with PS LG domains and single-site LG domain mutants. The molecular and biochemical knowledge obtained from this study will provide the basis for creation of a PS- derived FIXa-inhibiting molecule for the treatment of thrombotic conditions caused by PS deficiency or upregulation of FIXa.
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