Summary
The present review discusses the current concept of receptor-mediated clearance of coagulation factor VIII (FVIII) from the circulation in vivo, which is one of the mechanisms regulating FVIII level in plasma. Several lines of experimental evidence suggest that two receptors from the LDL receptor family, low-density lipoprotein receptor-related protein (LRP) and LDL receptor, cooperate in this process. Administration of receptor-associated protein, a classical antagonist of these receptors, leads to prolongation of FVIII half-life in mice.The elevation of FVIII level and prolongation of its mean residence time, recorded in conditional LRP-deficient mice, directly confirm the physiological role of LRP in mediating clearance of FVIII. Mice with combined LRP and low-density lipoprotein receptor (LDLR) deficiency show a further increase of FVIII level and more impressive, ~5-fold, prolongation of FVIII residence time in the circulation. Receptor-mediated clearance of FVIII is facilitated by heparan sulfate proteoglycans of extracellular matrix, which provide the initial binding of FVIII to the cell surface.We discuss the mapping of the major high-affinity LRP-binding sites to the regions 484-509 and 1811-1818 of A2 and A3 domains of FVIII, respectively; LDLR-binding sites are yet to be identified. Mutagenesis of these sites may result in disruption/reduction of FVIII/receptor interaction and consequently lead to clinically-significant prolongation of FVIII lifetime in the circulation.We demonstrate the feasibility of this approach by the results of Ala-scanning mutagenesis of the A2 LRP-binding site. Generation of a novel recombinant FVIII with prolonged lifetime would meet the demands, improve the efficacy and reduce the cost of FVIII replacement therapy of Hemophilia A.
Coagulation factor VIII (FVIII) [1] serves its function in the intrinsic coagulation pathway as a cofactor for the serine protease FIXa in activation of FX to FXa [1, 2]. Genetic or functional deficiency in FVIII phenotypically results in the bleeding disorder Hemophilia A, as the intrinsic pathway is responsible for normal spatial propagation of the clotting process from the surface of tissue factor-bearing cells.
The FVIII molecule (~300 kDa, 2332 amino acid residues) consists of three homologous A domains, two homologous C domains and the unique B domain (A1- A2-B-A3-C1-C2). In plasma, FVIII circulates as a metal ion-linked heterodimer consisting of the heavy chain (HCh),which is comprised of the A1 (1-336),A2 (373-719) and B domains (741-1648), and the light chain (LCh), which includes the A3 (1690- 2019), C1 (2020-2172) and C2 (2173-2332) domains.
In the circulation, FVIII is tightly non-covalently associated with its carrier protein von Willebrand factor (Kd ~ 0.4 nM),which prevents premature assembly of the Xase complex and protects FVIII from proteolytic inactivation [2, 3]. Limited proteolysis by physiological activators, thrombin or FXa, at Arg372 and Arg740 within FVIII HCh and at Arg1689 within LCh converts FVIII into its active form. In heterotrimeric activated FVIII, the A1 and A3 domains retain the metal ion bridge, and the relatively stable A1/A3-C1-C2 dimer is weakly associated with the A2 subunit through electrostatic interactions [1, 2].
The cofactor activity of FVIIIa in the assembled intrinsic Xase complex is provided by three essential interactions of FVIIIa: with the phospholipid membrane, with the enzyme FIXa and the substrate FX. The high-affinity interaction (Kd ~ 15 nM) between FVIIIa and FIXa is provided by residues 1811-1818 of the A3 domain of LCh [4]. Binding of the A2 domain to FIXa, although with low-affinity (Kd~300 nM), modulates the active site of FIXa and in this way amplifies the enzymatic activity of FIXa by 100-fold [5]. Specifically, the A2 residues 484-509 were shown to be involved in this interaction [6]. The FX-binding site was localized to A1 residues 349-372 of FVIII.
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Saenko, E.L. (2007). Regulation of Factor VIII Life-Cycle by Receptors from LDL Receptor Superfamily. In: Scharrer, I., Schramm, W. (eds) 36th Hemophilia Symposium Hamburg 2005. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-36715-4_4
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DOI: https://doi.org/10.1007/978-3-540-36715-4_4
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