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

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

› Author Affiliations

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

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