Abstract
Coagulation factor II, or prothrombin, is a multi-domain glycoprotein that is essential for life and a key target of anticoagulant therapy. In plasma, prothrombin circulates in two forms at equilibrium, “closed” (~80%) and “open” (~20%), brokered by the flexibility of the linker regions. Its structure remained elusive until recently when our laboratory solved the first X-ray crystal structure of the zymogen locked in the predominant closed form. Because of this technical breakthrough, fascinating aspects of the biology of prothrombin have started to become apparent, and with this, novel and important questions arise. Here, we examine the significance of the “closed”/“open” equilibrium in the context of the mechanism of thrombin generation. Further, we discuss the potential translational opportunities for the development of next-generation anticoagulants that arise from this discovery. By providing a structural overview of each alternative conformation, this minireview also offers a relevant example of modern structural biology and establishes a practical workflow to elucidate the structural features of analogous clotting and complement factors.
Highlights
In response to vascular injury, coagulation factor II (FII), or prothrombin, is converted to its active form thrombin by prothrombinase, a macromolecular complex composed of factor Xa, factor Va, calcium ions, and phospholipids [1]
Prothrombin is encoded by the F2 gene, which is located on the short arm of chromosome 11, at position 11.2 [6]
Analysis of the FRET histograms revealed that prothrombin exists in two forms at equilibrium, closed (∼80%) and open (∼20%) (Figure 1C) [32], and enabled the generation of structural models for each alternative conformation (Figure 1D)
Summary
In response to vascular injury, coagulation factor II (FII), or prothrombin, is converted to its active form thrombin by prothrombinase, a macromolecular complex composed of factor Xa (fXa), factor Va (fVa), calcium ions, and phospholipids [1]. Analysis of the FRET histograms revealed that prothrombin exists in two forms at equilibrium, closed (∼80%) and open (∼20%) (Figure 1C) [32], and enabled the generation of structural models for each alternative conformation (Figure 1D).
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