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On the target specificity of plasminogen activator inhibitor 1: the role of
heparin, vitronectin, and the reactive site
J Keijer, M Linders, JJ Wegman, HJ Ehrlich, K Mertens and H Pannekoek
Department of Molecular Biology, Central Laboratory of the Netherlands Red
Cross Blood Transfusion Service, Amsterdam.
Plasminogen activator inhibitor 1 (PAI-1) is the fast-acting inhibitor of
both tissue-type and urokinase-type plasminogen activators (t-PA, u- PA)
and is an essential regulatory protein of the fibrinolytic system. In the
presence of either the protein vitronectin or the glycosaminoglycan
heparin, PAI-1 is also an efficient inhibitor of thrombin. To assess
whether these cofactors turn PAI-1 into a general protease inhibitor or
whether their influence is restricted to thrombin, the second-order
association rate constants between PAI-1 and the human plasma proteases
t-PA, u-PA, plasmin, thrombin, Factor Xa (FXa), and Factor XIIa (FXIIa) in
the absence and in the presence of either vitronectin or heparin are
determined. In addition, the role of the PAI-1 reactive site P3 to P3'
residues for the specificity of inhibition was studied by using PAI-1
reactive site mutants. Our results show that: (1) Heparin exclusively
increases the rate of inhibition of thrombin by PAI-1, whereas in the
presence of heparin the rate of inhibition of the other proteases is not
altered; (2) Vitronectin is an obligatory cofactor for the inhibition of
thrombin by PAI-1. In addition, vitronectin moderately increases the rate
of inhibition by PAI-1 of u-PA and of plasmin, but does not alter the rate
of inhibition of t-PA, FXa, or FXIIa; (3) Apart from the important role of
the P1 residue, no consensus can be presented on the nature of other
residues within the P3 to P3' region with regard to target protease
specificity.
Volume 78,
Issue 5,
pp. 1254-1261,
09/01/1991
Copyright © 1991 by The American Society of Hematology
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