C4b-binding Protein Inhibits the Factor V-dependent but not the Factor V-independent Cofactor Activity of Protein S in the Activated Protein C-mediated Inactivation of Factor VIIIa

Robbert H. L. van de Poel; Joost C. M. Meijers; Bonno N. Bouma

doi:10.1055/s-0037-1615714

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2001; 85(05): 761-765
DOI: 10.1055/s-0037-1615714

Rapid Communication

Schattauer GmbH

C4b-binding Protein Inhibits the Factor V-dependent but not the Factor V-independent Cofactor Activity of Protein S in the Activated Protein C-mediated Inactivation of Factor VIIIa

Robbert H. L. van de Poel

¹Thrombosis and Haemostasis Laboratory, Department of Haematology, University Medical Center, Utrecht, Institute of Biomembranes, Utrecht University, Utrecht, The Netherlands

,

Joost C. M. Meijers

¹Thrombosis and Haemostasis Laboratory, Department of Haematology, University Medical Center, Utrecht, Institute of Biomembranes, Utrecht University, Utrecht, The Netherlands

²Present address: Dr. J. C. M. Meijers, Department of Vascular Medicine, Academic Medical Center, 1100 DD Amsterdam, The Netherlands

,

Bonno N. Bouma

¹Thrombosis and Haemostasis Laboratory, Department of Haematology, University Medical Center, Utrecht, Institute of Biomembranes, Utrecht University, Utrecht, The Netherlands

› Author Affiliations

Abstract

Summary

Activated protein C (APC) is an important inactivator of coagulation factors Va and VIIIa. In the inactivation of factors Va and VIIIa, protein S serves as a cofactor to APC. Protein S can bind to C4b-binding protein (C4BP), and thereby loses its cofactor activity to APC. By modulating free protein S levels, C4BP is an important regulator of protein S cofactor activity. In the factor VIIIa inactivation, protein S and factor V act as synergistic cofactors to APC. We investigated the effect of C4BP on both the factor V-independent and factor V-dependent cofactor activity of protein S in the factor VIIIa inactivation using a purified system. Protein S increased the APC-mediated inactivation of factor VIIIa to 60% and in synergy with protein S, factor V at equi-molar concentrations increased this effect further to 90%. The protein S/factor V synergistic effect was inhibited by preincubation of protein S and factor V with a four-fold molar excess of C4BP. However, C4BP did not inhibit the factor V-independent protein S cofactor activity in the purified system whereas it inhibited the cofactor activity in plasma. We conclude that C4BP-bound protein S retains its cofactor activity to APC in the factor VIIIa inactivation.

Keywords

C4b-binding protein - protein S - factor VIII - protein C - factor V

Full Text

References

References
1 Stenflo J. A new vitamin K-dependent protein. Purification from bovine plasma and preliminary characterization. J Biol Chem 1976; 251: 355-63.
2 Kisiel W, Canfield WM, Ericsson LH, Davie EW. Anticoagulant properties of bovine plasma protein C following activation by thrombin. Biochemistry 1977; 16: 5824-31.
3 Esmon CT, Owen WG. Identification of an endothelial cell cofactor for thrombin-catalyzed activation of protein C. Proc Natl Acad Sci U. S A 1981; 78: 2249-52.
4 Walker FJ, Sexton PW, Esmon CT. The inhibition of blood coagulation by activated Protein C through the selective inactivation of activated factor V. Biochim Biophys Acta 1979; 571: 333-42.
5 Kalafatis M, Mann KG. Role of the membrane in the inactivation of factor Va by activated protein C. J Biol Chem 1993; 268: 27246-4257.
6 Vehar GA, Davie EW. Preparation and properties of bovine factor VIII (antihemophilic factor). Biochemistry 1980; 19: 401-10.
7 Marlar RA, Kleiss AJ, Griffin JH. Mechanism of action of human activated protein C, a thrombin-dependent anticoagulant enzyme. Blood 1982; 59: 1067-72.
8 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: 4708-17.
9 Walker FJ. Regulation of activated protein C by a new protein. A possible function for bovine protein S. J Biol Chem 1980; 255: 5521-4.
10 Fulcher CA, Gardiner JE, Griffin JH, Zimmerman TS. Proteolytic inactivation of human factor VIII procoagulant protein by activated human protein C and its analogy with factor V. Blood 1984; 63: 486-9.
11 Walker FJ, Chavin SI, Fay PJ. Inactivation of factor VIII by activated protein C and protein S. Arch Biochem Biophys 1987; 252: 322-8.
12 Yegneswaran S, Wood GM, Esmon CT, Johnson AE. Protein S alters the active site location of activated protein C above the membrane surface. A fluorescence resonance energy transfer study of topography. J Biol Chem 1997; 272: 25013-21.
13 Mitchell CA, Kelemen SM, Salem HH. The anticoagulant properties of a modified form of protein S. Thromb Haemost 1988; 60: 298-304.
14 Heeb MJ, Mesters RM, Tans G, Rosing J, Griffin JH. Binding of protein S to factor Va associated with inhibition of prothrombinase that is independent of activated protein C. J Biol Chem 1993; 268: 2872-7.
15 Hackeng TM, van’t Veer C, Meijers JCM, Bouma BN. Human protein S inhibits prothrombinase complex activity on endothelial cells and platelets via direct interactions with factors Va and Xa. J Biol Chem 1994; 269: 21051-8.
16 Comp PC, Nixon RR, Cooper MR, Esmon CT. Familial protein S deficiency is associated with recurrent thrombosis. J Clin Invest 1984; 74: 2082-8.
17 Schwarz HP, Fischer M, Hopmeier P, Batard MA, Griffin JH. Plasma protein S deficiency in familial thrombotic disease. Blood 1984; 64: 1297-300.
18 Shen L, Dahlbäck B. Factor V and protein S as synergistic cofactors to activated protein C in degradation of factor VIIIa. J Biol Chem 1994; 269: 18735-8.
19 Dahlbäck B, Hildebrand B. Inherited resistance to activated protein C is corrected by anticoagulant cofactor activity found to be a property of factor V. Proc Natl Acad Sci U S A 1994; 91: 1396-400.
20 Dahlbäck B.. Inhibition of protein Ca cofactor function of human and bovine protein S by C4b-binding protein. J Biol Chem 1986; 261: 12022-7.
21 Nishioka J, Suzuki K. Inhibition of cofactor activity of protein S by a complex of protein S and C4b-binding protein. Evidence for inactive ternary complex formation between protein S, C4b-binding protein, and activated protein C. J Biol Chem 1990; 265: 9072-6.
22 Váradi K, Rosing J, Tans G, Pabinger I, Keil B, Schwarz HP. Factor V enhances the cofactor function of protein S in the APC-mediated inactivation of factor VIII: influence of the factor VR506Q mutation. Thromb Haemost 1996; 76: 208-14.
23 Hessing M, Kanters D, Hackeng TM, Bouma BN. Identification of different forms of human C4b-binding protein lacking β-chain and protein S binding ability. Thromb Haemost 1990; 64: 245-50.
24 Hackeng TM, Hessing M, van’t Veer C, Meijer Huizinga F, Meijers JCM, de Groot PG, van Mourik JA, Bouma BN. Protein S binding to human endothelial cells is required for expression of cofactor activity for activated protein C. J Biol Chem 1993; 268: 3993-4000.
25 van de Poel RHL, Meijers JCM, Bouma BN. Interaction between protein S and complement C4b-binding protein (C4BP). Affinity studies using chimeras containing C4BP β-chain short consensus repeats. J Biol Chem 1999; 274: 15144-50.
26 Klein JD, Walker FJ. Purification of a protein C activator from the venom of the southern copperhead snake (Agkistrodon contortrix contortrix). Biochemistry 1986; 25: 4175-9.
27 Kane WH, Majerus PW. Purification and characterization of human coagulation factor V. J Biol Chem 1981; 256: 1002-7.
28 van Wijnen M, Stam JG, Chang GTG, Meijers JCM, Reitsma PH, Bertina RM, Bouma BN. Characterization of mini-protein S, a recombinant variant of protein S that lacks the sex hormone binding globulin-like domain. Biochem J 1998; 330: 389-96.
29 van de Poel RHL, Meijers JCM, Rosing J, Tans G, Bouma BN. C4b-binding protein protects factor Va from inactivation by activated protein C. Biochemistry 2000; 39: 14543-8.
30 Koppelman SJ, Hackeng TM, Sixma JJ, Bouma BN. Inhibition of the intrinsic factor X activating complex by protein S: evidence for a specific binding of protein S to factor VIII. Blood 1995; 86: 1062-71.
31 Koppelman SJ, van’t Veer C, Sixma JJ, Bouma BN. Synergistic inhibition of the intrinsic factor X activation by protein S and C4b-binding protein. Blood 1995; 86: 2653-60.
32 Heeb MJ, Chang GTG, Bouma BN, Rosing J, Tans G, Griffin JH. C-terminal residues 621-635 of protein S are essential for binding to factor Va. J Biol Chem 1999; 274: 36187-92.
33 Nyberg P, Dahlbäck B, García de Frutos P. The SHBG-like region of protein S is crucial for factor V-dependent APC-cofactor function. FEBS Lett 1998; 433: 28-32.
34 Walker FJ. Characterization of a synthetic peptide that inhibits the interaction between protein S and C4b-binding protein. J Biol Chem 1989; 264: 17645-8.
35 Nelson RM, Long GL. Binding of protein S to C4b-binding protein. Muta-genesis of protein S. J Biol Chem 1992; 267: 8140-5.
36 Fernández JA, Heeb MJ, Griffin JH. Identification of residues 413-433 of plasma protein S as essential for binding to C4b-binding protein. J Biol Chem 1993; 268: 16788-94.
37 Chang GTG, Maas BH, Ploos van Amstel HK, Reitsma PH, Bertina RM, Bouma BN. Studies of the interaction between human protein S and human C4b-binding protein using deletion variants of recombinant human protein S. Thromb Haemost 1994; 71: 461-7.
38 Linse S, Härdig Y, Schultz DR, Dahlbäck B. A region of vitamin K-dependent protein S that binds to C4b binding protein (C4BP) identified using bacteriophage peptide display libraries. J Biol Chem 1997; 272: 14658-65.