Factor XI (fXI) is the zymogen of a plasma protease (fXIa) that contributes to hemostasis through proteolytic activation of factor IX. This reaction is required for sustained thrombin generation at a site of vascular injury to consolidate coagulation. FXIa has been implicated in the pathogenesis of thrombotic disease. FXI deficiency protects mice from vascular occlusion in arterial injury models, and protects protein C deficient mice from perinatal death due to disseminated coagulation. FXI differs significantly in structure from other coagulation proteases. The protein is a homodimer that lacks the phospholipid binding Gla-domain characteristic of coagulation proteases. FXI circulates in plasma in complex with the kinin precursor high molecular weight kininogen (HK). Each fXI polypeptide contains an N-terminal non-catalytic """"""""heavy chain"""""""" region and a C-terminal protease domain. The heavy chain contains four repeats called apple domains (designated Al to A4), that contain binding sites critical to protease function. The role of the dimeric structure of fXIa in protease activity has not been clearly delineated. There is also disagreement regarding the binding site for factor IX on the fXIa heavy chain. Similarly, there is conflicting data regarding binding of fXI and HK, an interaction that is necessary for fXI activation on platelets.
In Aim 1 of this proposal we will use standard SDS-PAGE, chromogenic substrate assays and steady state anisotropy to investigate factor IX activation by fXIa, and compare the results to those from a single chain variant of fXIa (fXIa/PKA4). We will also identify the apple domain that contains the substrate binding exosite, and identify the area of the factor IX Gla-domain that binds to fXIa.
In Aim 2 we will characterize binding interactions between the fXI Al domain and proteins thought to be required for proper fXI activation on platelets (prothrombin and thrombin), and determine the effects of mutations in these binding sites on fXI activation and activity on the platelet surface. The analysis will include an investigation into a possible role for the plasma protein a2 Glycoprotein 1 in regulating fXI activation on the platelet surface. Finally, in Aim 3, using normal and fXI-deficient mice, we will determine if fXI plays a role in the pathogenesis of disseminated intravascular coagulation induced by endotoxin infusion. The work will generate substantial new information regarding the activation and activity of a coagulation protease that is implicated in a variety of thrombotic disorders, and may identify fXIa as a potential target for therapeutic inhibition in consumptive coagulopathies.
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