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DOI: 10.1055/s-0037-1615833
Regulation of Factor VIIIa in the Intrinsic Factor Xase
Publication History
Publication Date:
09 December 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/199902/lookinside/thumbnails/10-1055-s-0037-1615833-1.jpg)
Introduction
Hemophilia A, the most common of the severe, inherited bleeding disorders, results from a deficiency or defect in the plasma protein factor VIII. The activated form of the protein serves as an essential cofactor for factor IXa in the conversion of factor X to factor Xa. This surface-bound complex of enzyme and cofactor is referred to as the intrinsic factor Xase. Factor VIIIa dramatically increases the catalytic rate constant for substrate conversion by an unclear mechanism. The activity and stability of the factor Xase appears to be regulated by the integrity of the cofactor. Factor VIIIa possesses a labile structure, and subunit dissociation results in the decay of Xase activity. Furthermore, factor VIIIa is a substrate for proteolytic inactivation by several enzymes, including factor IXa, the enzyme for which it serves as a cofactor. Although interest in the structure, function, and metabolism of factor VIII is commensurate with its biochemical and clinical importance, the molecular basis for its role in coagulation and the regulation of function through complex intramolecular and intermolecular interactions remain poorly understood.
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References:
- 1 Toole JJ, Knopf JL, Wozney Jm, Sultzman LA, Buecker JL, Pittmann DD, Kaufmam RJ, Brown E, Shoemaker C, Orr EC, Amphlett GW, Foster WB, Coe ML, Knutson GJ, Fass DN, Hewick RM. Molecular cloning of cDNA encoding human antihaemophilic factor. Nature 1984; 312: 342-347.
- 2 Wood WI, Capon DJ, Simonsen CC, Eaton DL, Gitschier J, Keyt B, Seeburg PH, Smith DH, Hollingshead P, Wion KL, Delwart E, Tuddenham EDG, Vehar GA, Lawn RM. Expression of active human factor VIII from recombinant DNA clones. Nature 1984; 312: 330-337.
- 3 Vehar GA, Keyt B, Eaton D, Rodriguez H, O’Brien DP, Rotblat F, Oppermann H, Keck R, Wood WI, Harkins RN, Tuddenham EGD, Lawn RM, Capon DJ. Structure of human factor VIII. Nature 1984; 312: 337-342.
- 4 Pan Y, DeFay T, Gitschier J, Cohen FE. Proposed structure of the A domains of factor VIII by homology modelling [letter]. Nat Struct Biol. 1995; 2: 740-744.
- 5 Pemberton S, Lindley P, Zaitsev V, Card G, Tuddenham EGD, Kemball-Cook G. A molecular model for the triplicated A domains of human factor VIII based on the crystal structure of human ceruloplasmin. Blood 1997; 89: 2413-2421.
- 6 Fass DN, Knutson GJ, Katzmann JA. Monoclonal antibodies to porcine factor VIII coagulant and their use in the isolation of active coagulant protein. Blood 1982; 59: 594-600.
- 7 Andersson LO, Forsman N, Huang K, Larsen K, Lundin A, Pavlu B, Sandberg H, Sewerin K, Smart J. Isolation and characterization of human factor VIII: molecular forms in commercial factor VIII concentrate, cryoprecipitate, and plasma. Proc Natl Acad Sci USA. 1986; 83: 2979-2983.
- 8 Fay PJ, Anderson MT, Chavin SI, Marder VJ. The size of human factor VIII heterodimers and the effects produced by thrombin. Biochim Biophys Acta. 1986; 871: 268-278.
- 9 Toole JJ, Pittman DD, Orr EC, Murtha P, Wasley LC, Kaufman RJ. A large region (approximately equal to 95 kDa) of human factor VIII is dispensable for in vitro procoagulant activity. Proc Natl Acad Sci USA. 1986; 83: 5939-5942.
- 10 Fay PJ, Smudzin TM. Characterization of the interaction between the A2 subunit and A1/A3-C1-C2 dimer in human factor VIIIa. J Biol Chem. 1992; 267: 13246-13250.
- 11 Esmon CT. The subunit structure of thrombin-activated factor V. Isolation of activated factor V, separation of subunits, and reconstitution of biological activity. J Biol Chem. 1979; 254: 964-973.
- 12 Nesheim ME, Foster WB, Hewick R, Mann KG. Characterization of factor V activation intermediates. J Biol Chem. 1984; 259: 3187-3196.
- 13 Fay PJ. Reconstitution of human factor VIII from isolated subunits. Arch Biochem Biophys. 1988; 262: 525-531.
- 14 Nordfang O, Ezban M. Generation of active coagulation factor VIII from isolated subunits. J Biol Chem. 1988; 263: 1115-1118.
- 15 Bihoreau N, Pin S, Kersabiec AMD, Vodot F, Fontaine-Aupart MP. Copper-atom identification in the active and inactive forms of plasma-derived FVIII and recombinant FVIII-ΔII. Eur J Biochem. 1994; 220: 41-48.
- 16 Tagliavacca L, Moon N, Dunham WR, Kaufman RJ. Identification and functional requirement of Cu(I) and its ligands within coagulation factor VIII. J Biol Chem. 1997; 272: 27428-27434.
- 17 Mann KG, Lawler CM, Vehar GA, Church WR. Coagulation factor V contains copper ion. J Biol Chem. 1984; 259: 12949-12951.
- 18 Sudhakar K, Fay PJ. Effects of copper on the structure and function of factor VIII subunits: evidence for an auxiliary role for copper ions in cofactor activity. Biochemistry. 1998; 37: 6874-6882.
- 19 Eaton D, Rodriguez H, Vehar GA. Proteolytic processing of human factor VIII. Correlation of specific cleavages by thrombin, factor Xa, and activated protein C with activation and inactivation of factor VIII coagulant activity. Biochemistry. 1986; 25: 505-512.
- 20 Regan LM, Fay PJ. Cleavage of factor VIII light chain is required for maximal generation of factor VIIIa activity. J Biol Chem. 1995; 270: 8546-8552.
- 21 Donath MS, Lenting PJ, van Mourik JA, Mertens K. The role of cleavage of the light chain at positions Arg1689 or Arg1721 in subunit interaction and activation of human blood coagulation factor VIII. J Biol Chem. 1995; 270: 3648-3655.
- 22 Hill-Eubanks DC, Parker CG, Lollar P. Differential proteolytic activation of factor VIII-von Willebrand factor complex by thrombin. Proc Natl Acad Sci USA. 1989; 86: 6508-6512.
- 23 Lollar P, Parker CG. Subunit structure of thrombin-activated porcine factor VIII. Biochemistry. 1989; 28: 666-674.
- 24 Fay PJ, Haidaris PJ, Smudzin TM. Human factor VIIIa subunit structure. Reconstitution of factor VIIIa from the isolated A1/A3-C1-C2 dimer and A2 subunit. J Biol Chem. 1991; 266: 8957-8962.
- 25 Pittman DD, Millenson M, Marquette K, Bauer K, Kaufman RJ. A2 domain of human recombinant-derived factor VIII is required for procoagulant activity but not for thrombin cleavage. Blood 1992; 79: 389-397.
- 26 Lollar P, Parker ET, Fay PJ. Coagulant properties of hybrid human/porcine factor VIII molecules. J Biol Chem. 1992; 267: 23652-23657.
- 27 Persson E, Ezban M, Shymko RM. Kinetics of the interaction between the human factor VIIIa subunits: effects of pH, ionic strength, calcium concentration, heparin and activated protein C-catalyzed proteolysis. Biochemistry. 1995; 34: 12775-12781.
- 28 Fay PJ, Smudzin TM, Walker FJ. Activated protein C-catalyzed inactivation of human factor VIII and factor VIIIa. Identification of cleavage sites and correlation of proteolysis with cofactor activity. J Biol Chem. 1991; 266: 20139-20145.
- 29 Fay PJ, Haidaris PJ, Huggins CF. Role of the COOH-terminal acidic region of A1 subunit in A2 subunit retention in human factor VIIIa. J Biol Chem. 1993; 268: 17861-17866.
- 30 Parker ET, Pohl J, Blackburn MN, Lollar P. Subunit structure and function of porcine factor Xa-activated factor VIII. Biochemistry. 1997; 36: 9365-9373.
- 31 Curtis JE, Helgerson SL, Parker ET, Lollar P. Isolation and characterization of thrombin-activated human factor VIII. J Biol Chem. 1994; 269: 6246-6251.
- 32 Sudhakar K, Fay PJ. Exposed hydrophobic sites in factor VIII and isolated subunits. J Biol Chem. 1996; 271: 23015-23021.
- 33 O’Brien LM, Huggins CF, Fay PJ. Interacting regions in the A1 and A2 subunits of factor VIIIa identified by zero-length cross-linking. Blood 1997; 90: 3943-3950.
- 34 Gilbert GE, Arena AA. Activation of the factor VIIIa-factor IXa enzyme complex of blood coagulation by membranes containing phosphatidyl-L-serine. J Biol Chem. 1996; 271: 11120-11125.
- 35 Lenting PJ, Donath MJ, van Mourik JA, Mertens K. Identification of a binding site for blood coagulation factor IXa on the light chain of human factor VIII. J Biol Chem. 1994; 269: 7150-7155.
- 36 Duffy EJ, Parker ET, Mutucumarana VP, Johnson AE, Lollar P. Binding of factor VIIIa and factor VIII to factor IXa on phospholipid vesicles. J Biol Chem. 1992; 267: 17006-17011.
- 37 Lenting PJ, van de Loo JW, Donath MJ, van Mourik JA, Mertens K. The sequence Glu1811-Lys1818 of human blood coagulation factor VIII comprises a binding site for activated factor IX. J Biol Chem. 1996; 271: 1935-1940.
- 38 Regan LM, Lamphear BJ, Huggins CF, Walker FJ, Fay PJ. Factor IXa protects factor VIIIa from activated protein C. Factor IXa inhibits activated protein C-catalyzed cleavage of factor VIIIa at Arg562. J Biol Chem. 1994; 269: 9445-9452.
- 39 Fay PJ, Beattie T, Huggins CF, Regan LM. Factor VIIIa A2 subunit residues 558-565 represent a factor IXa interactive site. J Biol Chem. 1994; 269: 20522-20527.
- 40 O’Brien LM, Medved LV, Fay PJ. Localization of factor IXa and factor VIIIa interactive sites. J Biol Chem. 1995; 270: 27087-27092.
- 41 Kemball-Cook G, Tuddenham EG. The factor VIII mutation database on the World Wide Web: the haemophilia A mutation, search, test and resource site. HAMSTeRS update (version 3.0). Nucleic Acids Res. 1997; 25: 128-132.
- 42 Amano K, Sarkar R, Pemberton S, Kemball-Cook G, Kazazian Jr. HH, Kaufman RJ. The molecular basis for cross-reacting material-positive hemophilia A due to missense mutations within the A2-domain of factor VIII. Blood 1998; 91: 538-548.
- 43 Fay P J, Koshibu K. The A2 subunit of factor VIIIa modulates the active site of factor IXa. J Biol Chem. 1998; 273: 19049-19054.
- 44 Fay PJ, Koshibu K, Mastri M. The A1 and A2 subunits of factor VIIIa synergistically stimulate factor IXa catalytic activity. J. Biol. Chem. 1999; 274: 15401-15406.
- 45 Christophe OD, Lenting PJ, Kolkman JA, Brownlee GG, Mertens K. Blood coagulation factor IX residues Glu78 and Arg94 provide a link between both epidermal growth factor-like domains that is crucial in the interaction with factor VIII light chain. J Biol Chem. 1998; 273: 222-227.
- 46 Bajaj SP, Rapaport SI, Maki SL. A monoclonal antibody to factor IX that inhibits the factor VIII:Ca potentiation of factor X activation. J Biol Chem. 1985; 260: 11574-11580.
- 47 Brandstetter H, Bauer M, Huber R, Lollar P, Bode W. X-ray structure of clotting factor IXa: active site and module structure related to Xase activity and hemophilia B. Proc Natl Acad Sci USA. 1995; 92: 9796-9800.
- 48 Mutucumarana VP, Duffy EJ, Lollar P, Johnson AE. The active site of factor IXa is located far above the membrane surface and its conformation is altered upon association with factor VIIIa. A fluorescence study. J Biol Chem. 1992; 267: 17012-17021.
- 49 Foster PA, Fulcher CA, Houghten RA, Zimmerman TS. Synthetic factor VIII peptides with amino acid sequences contained within the C2 domain of factor VIII inhibit factor VIII binding to phosphatidylserine. Blood 1990; 75: 1999-2004.
- 50 Lapan KA, Fay PJ. Localization of a factor X interactive site in the A1 subunit of factor VIIIa. J Biol Chem. 1997; 272: 2082-2088.
- 51 Regan LM, O’Brien LM, Beattie TL, Sudhakar K, Walker FJ, Fay PJ. Activated protein C-catalyzed proteolysis of factor VIIIa alters its interactions within factor Xase. J Biol Chem. 1996; 271: 3982-3987.
- 52 Lapan KA, Fay PJ. Interaction of the A1 subunit of factor VIIIa and the serine protease domain of factor X identified by zero-length cross-linking. Thromb Haemost. 1998; 80: 418-422.
- 53 Rawala-Sheikh R, Ahmad SS, Ashby B, Walsh PN. Kinetics of coagulation factor X activation by platelet-bound factor IXa. Biochemistry. 1990; 29: 2606-2611.
- 54 Gilbert GE, Arena AA. Partial activation of the factor VIIIa-factor IXa enzyme complex by dihexanoic phosphatidylserine at submicellar concentrations. Biochemistry. 1997; 36: 10768-10776.
- 55 Mathur A, Zhong D, Sabharwal AK, Smith KJ, Bajaj SP. Interaction of factor IXa with factor VIIIa. Effects of protease domain Ca2+ binding site, proteolysis in the autolysis loop, phospholipid, and factor X. J Biol Chem. 1997; 272: 23418-23426.
- 56 Lollar P, Parker ET, Curtis JE, Helgerson SL, Hoyer LW, Scott ME, Scandella D. Inhibition of human factor VIIIa by anti-A2 subunit antibodies. J Clin Invest. 1994; 93: 2497-2504.
- 57 Jesty J. Analysis of the generation and inhibition of factor Xa. Area under generation curves is independent of enzyme generation rate. J Biol Chem. 1990; 265: 17539-17544.
- 58 Lollar P, Knutson GJ, Fass DN. Stabilization of thrombin-activated porcine factor VIII:C by factor IXa phospholipid. Blood 1984; 63: 1303-1308.
- 59 Lamphear BJ, Fay PJ. Factor IXa enhances reconstitution of factor VIIIa from isolated A2 subunit and A1/A3-C1-C2 dimer. J Biol Chem. 1992; 267: 3725-3730.
- 60 O’Brien DP, Johnson D, Byfield P, Tuddenham EG. Inactivation of factor VIII by factor IXa. Biochemistry. 1992; 31: 2805-2812.
- 61 Lamphear BJ, Fay PJ. Proteolytic interactions of factor IXa with human factor VIII and factor VIIIa. Blood 1992; 80: 3120-3126.
- 62 Fay PJ, Beattie TL, Regan LM, O’Brien LM, Kaufman RJ. Model for the factor VIIIa-dependent decay of the intrinsic factor Xase. Role of subunit dissociation and factor IXa-catalyzed proteolysis. J Biol Chem. 1996; 271: 6027-6032.
- 63 Lawson JH, Kalafatis M, Stram S, Mann KG. A model for the tissue factor pathway to thrombin. I. An empirical study. J Biol Chem. 1994; 269: 23357-23366.
- 64 Jones KC, Mann KG. A model for the tissue factor pathway to thrombin. II. A mathematical simulation. J Biol Chem. 1994; 269: 23367-23373 Errata. J Biol Chem. 1995;270(15)9026.
- 65 Pipe SW, Eickhorst AN, McKinley SH, Saenko EL, Kaufman RJ. Mild hemophilia A caused by increased rate of factor VIII A2 subunit dissociation: evidence for nonproteolytic inactivation of factor VIII in vivo. Blood 1999; 93: 176-183.
- 66 Pipe SW, Kaufman RJ. Characterization of a genetically engineered inactivation-resistant coagulation factor VIIIa. Proc Natl Acad Sci USA. 1997; 94: 11851-11856.
- 67 Dahlback B. The protein C anticoagulant system: inherited defects as basis for venous thrombosis. [Review] [308 refs]. Thromb Res. 1995; 77: 1-43.
- 68 Lu D, Kalafatis M, Mann KG, Long GL. Comparison of activated protein C/protein S-mediated inactivation of human factor VIII and factor V. Blood 1996; 87: 4708-4717.
- 69 O’Brien LM, Fay PJ. Effect of protein S on factor VIIIa cleavage by human activated protein C. Blood 1998; 92 (Suppl. 01) 353a.
- 70 van ‘t Veer C Golden NJ, Kalafatis M, Mann KG. Inhibitory mechanism of the protein C pathway on tissue factor-induced thrombin generation. Synergistic effect in combination with tissue factor pathway inhibitor. J Biol Chem. 1997; 272: 7983-7994.