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Title: A monoclonal antibody directed against an epitope in the NH2-terminal region of native human plasminogen induces a modification of its functional properties
Authors: Mirshahi, M ×
Soria, J
Lijnen, Roger
Fleury, V
Bertrand, O
Drouet, L
Caen, JP
Soria, C #
Issue Date: 1997
Publisher: Harcourt
Series Title: Fibrinolysis: An International Journal of Fibrinolysis and Thrombolysis vol:11 issue:3 pages:155-163
Conference: date:UNIV ROUEN,FAC MED & PHARM,LAB DIFEMA,ST ETIENNE,FRANCE; HOP HOTEL DIEU,LAB ST MARIE,PARIS,FRANCE; CATHOLIC UNIV LEUVEN,CTR MOL & VASC BIOL,B-3000 LOUVAIN,BELGIUM; HOP LARIBOISIERE,IVS,F-75475 PARIS,FRANCE; INSERM,U76,PARIS,FRANCE
Abstract: A monoclonal antibody (MAb A1D12) that is directed against an epitope localized in the amino acid sequence Arg(68)-Lys(77) of human plasminogen was identified. Binding of MAb A1D12 to native plasminogen resulted in a 2- to 3-fold enhanced plasminogen activation by various plasminogen activators and an up to 2-fold enhanced binding to fibrin(ogen). Consequently, MAb A1D12 potentiated the fibrinolysis in human plasma induced by single-chain urokinase-type plasminogen activator (scu-PA), two-chain urokinase-type plasminogen activator (tcu-PA), streptokinase (SK) and tissue-type plasminogen activator (t-PA), each to a different degree. Incorporation of both MAb A1D12 (at 200 mu g/ml) and the plasminogen activator in human plasma before clotting resulted in enhanced subsequent lysis as compared to the absence of MAb: release of fibrin D-dimer after incubation for 15 min at 37 degrees C was enhanced 50-fold for tcu-PA, 15 to 20-fold for SK and only 3-fold for t-PA. The generation of fibrin D-dimer from whole blood clots submerged for 100 min at 37 degrees C in normal human plasma containing 150 mu g/ml of MA6 A1D12 was enhanced 2 to 3-fold, e-fold or 1.5-fold (as compared to the absence of MAb) for scu-PA, tcu-PA, and SK, respectively. Fibrin D dimer levels were not significantly increased for t-PA. The differential effects of MAb A1D12 on the fibrinolytic potential of scu-PA, tcu-PA, SK or t-PA may be related to the different mechanism of action of these plasminogen activators. The effects of MAb A1D12 on the functional properties of plasminogen may be due to a conformational change from a tight spiral structure in native plasminogen to a more open structure. Thereby, an intramolecular interaction between the NH2-terminal pre-activation peptide and the kringle and/or proteinase domains is disrupted, resulting in a better accessibility of the Arg(561)-Val(562) peptide bond for plasminogen activators and of the lysine-binding sites in the kringle domains for binding to fibrin. These data thus confirm the functional importance of this intramolecular interaction in plasminogen and establish that it involves the region comprising amino acids Arg(68) through Lys(77).
ISSN: 0268-9499
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular and Vascular Biology
× corresponding author
# (joint) last author

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