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The interaction of plasminogen activator inhibitor 1 with plasminogen
activators (tissue-type and urokinase-type) and fibrin: localization of
interaction sites and physiologic relevance
J Keijer, M Linders, AJ van Zonneveld, HJ Ehrlich, JP de Boer and H Pannekoek
Department of Molecular Biology, Central Laboratory of the Netherlands Red
Cross Blood Transfusion Service, Amsterdam.
Plasminogen activator inhibitor 1 (PAI-1), an essential regulatory protein
of the fibrinolytic system, harbors interaction sites for plasminogen
activators (tissue-type [t-PA] and urokinase-type [u-PA]) and for fibrin.
In this study, anti-PAI-1 monoclonal antibodies (MoAbs) were used to
identify interaction sites of PAI-1 with these components. The binding
sites of 18 different MoAbs were established and are located on five
distinct "linear" areas of PAI-1. MoAbs, binding to two distinct areas of
PAI-1, are able to prevent the inhibition of t-PA by PAI-1. In addition,
two interaction sites for fibrin were identified on PAI-1. The area located
between amino acids 110 and 145 of PAI-1 contains a binding site for both
components and its significance is discussed in the context of the t-PA
inhibition by fibrin-bound PAI-1. Subsequently, the MoAbs were used to
assess the role of platelet-PAI-1 in clot-lysis. An in vitro clot-lysis
system was used to demonstrate that clot-lysis resistance is dependent on
the presence of activated platelets and that PAI-1 is a major determinant
for lysis-resistance. We propose that, upon activation of platelets, PAI-1
is fixed within the clot by binding to fibrin and retains its full capacity
to inhibit t-PA and u-PA.
Volume 78,
Issue 2,
pp. 401-409,
07/15/1991
Copyright © 1991 by The American Society of Hematology
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