Oxidized low-density lipoprotein associates strongly with carboxy-terminal domain of tissue factor pathway inhibitor and reduces the catalytic activity of the protein

Thromb Haemost. 2002 Jan;87(1):80-5.

Abstract

Tissue factor pathway inhibitor (TFPI) is a physiological protease inhibitor of the extrinsic blood coagulation pathway. Previously we have shown that TFPI associates quite rapidly with oxidized low-density lipoprotein (ox-LDL), with a reduction of the inhibitory activity on factor X activation. In the present study, it was found, by means of agarose gel electrophoresis, that the pre-incubation of full-length rTFPI with heparin or the carboxy (C)-terminal part (peptide 240-265) of TFPI prevented the association with ox-LDL in a dose-dependent manner. When rTFPI lacking the C-terminal basic part of the molecule (rTFPI-C) was mixed with ox-LDL, only a small amount of rTFPI-C was shifted to the position of ox-LDL on electrophoresis. Further, ox-LDL did not reduce the activity of rTFPI-C. These results indicate that the C-terminal domain of TFPI molecule plays a predominant role in the binding to ox-LDL and the binding through the C-terminal part is essential for the ox-LDL-dependent reduction of the anticoagulant activity of TFPI.

MeSH terms

  • Antibody Specificity
  • Anticoagulants / pharmacology
  • Antigens / drug effects
  • Antigens / immunology
  • Blood Protein Electrophoresis
  • Electrophoresis, Agar Gel
  • Heparin / pharmacology
  • Humans
  • Lipoproteins / antagonists & inhibitors
  • Lipoproteins / chemistry
  • Lipoproteins / immunology
  • Lipoproteins / metabolism*
  • Lipoproteins, LDL / chemistry
  • Lipoproteins, LDL / metabolism*
  • Lipoproteins, LDL / pharmacology
  • Peptide Fragments / chemistry
  • Peptide Fragments / metabolism
  • Protein Binding
  • Protein Interaction Mapping
  • Protein Structure, Tertiary
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / metabolism

Substances

  • Anticoagulants
  • Antigens
  • Lipoproteins
  • Lipoproteins, LDL
  • Peptide Fragments
  • Recombinant Fusion Proteins
  • lipoprotein-associated coagulation inhibitor
  • oxidized low density lipoprotein
  • Heparin