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Binding sites for blood coagulation factor Xa and protein S involving residues 493-506 in factor Va

Academic Article
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Overview

authors

  • Heeb, Mary Jo
  • Kojima, Y.
  • Hackeng, T. M.
  • Griffin, John

publication date

  • September 1996

journal

  • Protein Science  Journal

abstract

  • Inactivation due to cleavage of Factor Va (FVa) at Arg 506 by activated protein C (APC) helps to downregulate blood coagulation. To identify potential functional roles of amino acids near Arg 506, synthetic overlapping pentadecapeptides comprising FVa heavy chain residues 481-525 were tested for their ability to inhibit prothrombin activation by prothrombinase complexes [Factor Xa (FXa):FVa:phospholipids:Ca2+]. The most potent inhibition was observed for peptide VP493 (residues 493-506), with 50% inhibition at 2.5 microM. VP493 also inhibited FXa in plasma in FXa-1-stage clotting assays by 50% at 3 microM. When the C-terminal carboxamide group of VP493 was replaced by a carboxyl group, most prothrombinase inhibitory activity was lost. VP493 preincubated with FXa inhibited prothrombinase with a pattern of mixed inhibition. Homologous peptides from Factor VIII sequences did not inhibit prothrombinase. Affinity-purified antibodies to VP493 inhibited prothrombinase activity and prolonged FXa-1-stage clotting times. VP493 also blocked the ability of protein S to inhibit prothrombinase independently of APC. Immobilized VP493 bound specifically with similar affinity to both FXa and protein S (Kd approximately 40 nM), but did not measurably bind prothrombin or APC. These studies suggest that FVa residues 493-506 contribute to binding sites for both FXa and protein S, providing a rationale for the ability of protein S to negate the protective effect of FXa toward APC cleavage of FVa. Possible loss of this FVa binding site for FXa due to cleavage at Arg 506 by APC may help explain why this cleavage causes 40% decrease in FVa activity and facilitates inactivation of FVa.

subject areas

  • Amino Acid Sequence
  • Antibodies
  • Anticoagulants
  • Binding Sites
  • Enzyme Inhibitors
  • Factor Va
  • Factor Xa
  • Factor Xa Inhibitors
  • Humans
  • Molecular Sequence Data
  • Peptide Fragments
  • Protein S
  • Thromboplastin
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Research

keywords

  • Factor Va
  • Factor Xa
  • anticoagulant
  • blood coagulation
  • protein S
  • protein-protein interaction
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Identity

PubMed Central ID

  • PMC2143529

International Standard Serial Number (ISSN)

  • 0961-8368

Digital Object Identifier (DOI)

  • 10.1002/pro.5560050914

PubMed ID

  • 8880912
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Additional Document Info

start page

  • 1883

end page

  • 1889

volume

  • 5

issue

  • 9

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