Multimerin 1 binds factor V and activated factor V with high affinity and inhibits thrombin generation

Samira B. Jeimy; Nola Fuller; Subia Tasneem; Kenneth Segers; Alan R. Stafford; Jeffrey I. Weitz; Rodney M. Camire; Gerry A. F. Nicolaes; Catherine P. M. Hayward

doi:10.1160/TH08-05-0307

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2008; 100(06): 1058-1067
DOI: 10.1160/TH08-05-0307

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Multimerin 1 binds factor V and activated factor V with high affinity and inhibits thrombin generation

Authors

Samira B. Jeimy

¹Department of Pathology and Molecular Medicine, Health Sciences Center, McMaster University, Hamilton, Ontario, Canada
Nola Fuller

¹Department of Pathology and Molecular Medicine, Health Sciences Center, McMaster University, Hamilton, Ontario, Canada
Subia Tasneem

¹Department of Pathology and Molecular Medicine, Health Sciences Center, McMaster University, Hamilton, Ontario, Canada
Kenneth Segers

²Cardiovascular Research Institute, Maastricht Department of Biochemistry, Maastricht University, Maastricht, The Netherlands
Alan R. Stafford

³Department of Medicine, McMaster University and Henderson Research Centre, Hamilton, Ontario, Canada
Jeffrey I. Weitz

³Department of Medicine, McMaster University and Henderson Research Centre, Hamilton, Ontario, Canada
Rodney M. Camire

⁴Department of Pediatrics, Division of Hematology, Children’s Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
Gerry A. F. Nicolaes

²Cardiovascular Research Institute, Maastricht Department of Biochemistry, Maastricht University, Maastricht, The Netherlands
Catherine P. M. Hayward

¹Department of Pathology and Molecular Medicine, Health Sciences Center, McMaster University, Hamilton, Ontario, Canada

Abstract

Summary

Multimerin 1 (MMRN1) is a polymeric, factorV (FV) binding protein that is stored in platelet and endothelial cell secretion granules but is undetectable in normal plasma. In human platelet α-granules, FV is stored complexed to MMRN1, predominantly by noncovalent binding interactions. The FV binding site for MMRN1 is located in the light chain, where it overlaps the C1 and C2 domain membrane binding sites essential for activated FV (FVa) procoagulant function. Surface plasmon resonance (SPR), circular dichroism (CD) and thrombin generation assays were used to study the binding of FV and FVa to MMRN1, and the functional consequences. FV and FVa bound MMRN1 with high affinities (KD:2 and 7 nM, respectively). FV dissociated more slowly from MMRN1 than FVa in SPR experiments, and CD analyses suggested greater conformational changes in mixtures of FV and MMRN1 than in mixtures of FV and MMRN1. SPR analyses indicated that soluble phosphatidylserine (1,2-Dicaproylsn-glycero-3-phospho-L-serine) competitively inhibited both FV-MMRN1 and FVa-MMRN1 binding. Furthermore, exogenous MMRN1 delayed and reduced thrombin generation by plasma and platelets, and it reduced thrombin generation by preformed FVa. Exogenous MMRN1 also delayed FV activation, triggered by adding tissue factor to plasma, or by adding purified thrombin or factor Xa to purified FV. The high affinity binding of FV to MMRN1 may facilitate the costorage of the two proteins in platelet α-granules. As a consequence, MMRN1 release during platelet activation may limit platelet dependent thrombin generation in vivo.

Keywords

Coagulation factors - coagulation inhibitors - platelet physiology

Full Text

References

References
1 Jeimy SB, Tasneem S, Cramer EM. et al. Multimerin 1. Platelets 2008; 19: 83-95.
2 Hayward CP, Fuller N, Zheng S. et al. Human platelets contain forms of factor V in disulfide-linkage with multimerin. Thromb Haemost 2004; 92: 1349-1357.
3 Suehiro Y, Veljkovic DK, Fuller N. et al. Endocytosis and storage of plasma factor V by human megakaryocytes. Thromb Haemost 2005; 94: 585-592.
4 Bouchard BA, Williams JL, Meisler NT. et al. Endocytosis of plasma-derived factor V by megakaryocytes occurs via a clathrin-dependent, specific membrane binding event. J Thromb Haemost 2005; 30: 541-551.
5 Kane WH Factor V. In: Hemostasis and Thrombosis: Basic Principles and Clinical Practice, 4th ed. Philadelphia: J.B. Lippincott Company; 2006: 177-192.
6 Jeimy SB, Woram RA, Fuller N. et al. Identification of the MMRN1 binding region within the C2 domain of human factor V. J Biol Chem 2004; 279: 51466-51471.
7 Jeimy SB, Quinn-Allen MA, Fuller N. et al. Location of the multimerin 1 binding site in coagulation factor V: an update. Thromb Res 2008. epub ahead of print.
8 Gilbert GE, Kaufman RJ, Arena AA. et al. Four hydrophobic amino acids of the factor VIII C2 domain are constituents of both the membrane-binding and von Willebrand factor-binding motifs. J Biol Chem 2002; 277: 6374-6381.
9 Jacquemin M, Benhida A, Peerlinck K. et al. A human antibody directed to the factor VIII C1 domain inhibits factor VIII cofactor activity and binding to von Willebrand factor. Blood 2000; 95: 156-163.
10 Ganz PR, Atkins JS, Palmer DS. et al. Definition of the affinity of binding between human von Willebrand factor and coagulation factor VIII. Biochem Biophys Res Commun 1991; 180: 231-237.
11 Saenko EL, Scandella D. The acidic region of the factor VIII light chain and the C2 domain together form the high affinity binding site for von Willebrand factor. J Biol Chem 1997; 272: 18007-18014.
12 Vlot AJ, Koppelman SJ, van den Berg MH. et al. The affinity and stoichiometry of binding of human factor VIII to von Willebrand factor. Blood 1995; 85: 3150-3157.
13 Allen GA, Wolberg AS, Oliver JA. et al. Impact of procoagulant concentration on rate, peak and total thrombin generation in a model system. J Thromb Haemost 2004; 20: 402-413.
14 Hemker HC, Giesen P, AlDieri R. et al. The calibrated automated thrombogram (CAT): a universal routine test for hyper and hypocoagulability. Pathophysiol Haemost Thromb 2002; 32: 249-253.
15 Mann KG. How much factor V is enough?. Thromb Haemost 2000; 83: 3-4.
16 Jeimy SB, Krakow EF, Fuller N. et al. An acquired factor V inhibitor associated with defective factor V function, storage and binding to multimerin 1. J Thromb Haemost 2008; 06: 395-397.
17 Majumder R, Weinreb G, Zhai X. et al. Soluble phosphatidylserine triggers assembly in solution of a prothrombin-activating complex in the absence of a membrane surface. J Biol Chem 2002; 277: 29765-29773.
18 Koppaka V, Wang J, Banerjee M. et al. Soluble phospholipids enhance factor Xa-catalyzed prothrombin activation in solution. Biochemistry 1996; 35: 7482-7491.
19 Zhai X, Srivastava A, Drummond DC. et al. Phosphatidylserine binding alters the conformation and specifically enhances the cofactor activity of bovine factor Va. Biochemistry 2002; 41: 5675-5684.
20 Selo I, Negroni L, Creminon C. et al. Preferential labeling of alpha-amino N-terminal groups in peptides by biotin: application to the detection of specific antipeptide antibodies by enzyme immunoassays. J Immunol Methods 1996; 199: 127-138.
21 Nicolaes GA, Tans G, Thomassen MC. et al. Peptide bond cleavages and loss of functional activity during inactivation of factor Va and factor VaR506Q by activated protein C. J Biol Chem 1995; 270: 21158-21166.
22 Rosing J, Bakker HM, Thomassen MC. et al. Characterization of two forms of human factor Va with different cofactor activities. J Biol Chem 1993; 268: 21130-21136.
23 Toso R, Camire RM. Removal of B-domain sequences from factor V rather than specific proteolysis underlies the mechanism by which cofactor function is realized. J Biol Chem 2004; 279: 21643-21650.
24 Day YS, Baird CL, Rich RL. et al. Direct comparison of binding equilibrium, thermodynamic, and rate constants determined by surface-and solution-based biophysical methods. Protein Sci 2002; 11: 1017-1025.
25 Drake AW, Myszka DG, Klakamp SL. Characterizing high-affinity antigen/antibody complexes by kinetic and equilibrium-based methods. Anal Biochem 2004; 328: 35-43.
26 Dahlback B. Interaction between vitamin K-dependent protein S and the complement protein, C4b-binding protein. A link between coagulation and the complement system. Semin Thromb Hemost 1984; 10: 139-148.
27 Srivastava A, Quinn-Allen MA, Kim SW. et al. Soluble phosphatidylserine binds to a single identified site in the C2 domain of human factor Va. Biochemistry 2001; 40: 8246-8255.
28 Grundy JE, Lavigne N, Hirama T. et al. Binding of plasminogen and tissue plasminogen activator to plasmin-modulated factor X and factor Xa. Biochemistry 2001; 40: 6293-6302.
29 van S Spoelder HJ, Bloemendal M. et al. Estimation of protein secondary structure and error analysis from circular dichroism spectra. Anal Biochem 1990; 191: 110-118.
30 Provencher SW, Glockner J. Estimation of globular protein secondary structure from circular dichroism. Biochemistry 1981; 20: 33-37.
31 Whitmore L, Wallace BA. DICHROWEB, an online server for protein secondary structure analyses from circular dichroism spectroscopic data. Nucleic Acids Res 2004; 32: W668-W673.
32 Johnson Jr WC. Protein secondary structure and circular dichroism:a practical guide. Proteins 1990; 07: 205-214.
33 Orfeo T, Brufatto N, Nesheim ME. et al. The factor V activation paradox. J Biol Chem 2004; 279: 19580-19591.
34 Bevers EM, Comfurius P, Zwaal RF. Changes in membrane phospholipid distribution during platelet activation. Biochim Biophys Acta 1983; 736: 57-66.
35 Keller FG, Ortel TL, Quinn-Allen MA. et al. Thrombin-catalyzed activation of recombinant human factor V. Biochemistry 1995; 34: 4118-4124.
36 Gould WR, Silveira JR, Tracy PB. Unique in vivo modifications of coagulation factor V producea physically and functionally distinct platelet-derived cofactor: characterization of purified platelet-derived factor V/Va. J Biol Chem 2004; 279: 2383-2393.
37 Koedam JA, Hamer RJ, Beeser-Visser NH. et al. The effect of von Willebrand factor on activation of factor VIII by factor Xa. Eur J Biochem 1990; 189: 229-234.
38 Adam F, Zheng S, Joshi N. et al. Analyses of cellular multimerin1 receptors: in vitro evidence of binding mediated by alphaIIbbeta3 and alphavbeta3. Thromb Haemost 2005; 94: 1004-1011.
39 Hayward CP, Furmaniak-Kazmierczak E, Cieutat AM. et al. Factor V is complexed with multimerin in resting platelet lysates and colocalizes with multimerin in platelet alpha-granules. J Biol Chem 1995; 270: 19217-19224.
40 Hoekema L, Nicolaes GA, Hemker HC. et al. Human factor Va1 and factor Va2: properties in the procoagulant and anticoagulant pathways. Biochemistry 1997; 36: 3331-3335.
41 Laue TM, Lu R, Krieg UC. et al. Ca2+-dependent structural changes in bovine blood coagulation factor Va and its subunits. Biochemistry 1989; 28: 4762-4771.