Modulation of heparin cofactor II function by S protein (vitronectin) and formation of a ternary S protein-thrombin-heparin cofactor II complex.
The complement inhibitor S protein, which is identical to the adhesive protein vitronectin, functions as heparin-neutralizing factor by protecting thrombin as well as factor Xa against fast inactivation by antithrombin III. The interference of S protein with glycosaminoglycan-catalyzed inhibition of thrombin by heparin cofactor II was investigated in these studies. S protein significantly counteracted the anticoagulant activity of heparin and pentosan polysulfate but not of dermatan sulfate. In the presence of 0.3 micrograms/ml heparin, 0.5 micrograms/ml pentosan polysulfate, or 2 micrograms/ml dermatan sulfate, S protein induced a concentration-dependent reduction of the inhibition rate of thrombin by heparin cofactor II. This resulted in a decrease of the apparent pseudo first-order rate constants by about 17-fold (heparin), or about 7-fold (pentosan polysulfate), whereas no neutralization of dermatan sulfate was demonstrable at a physiological ratio of S protein to heparin cofactor II. Exposure of the glycosaminoglycan-binding region of S protein by reduction and carboxymethylation of the protein increased the neutralizing activity of S protein towards heparin and pentosan polysulfate. The results of these functional experiments correlated well with the demonstration of direct binding of S protein to both polysaccharides but not to dermatan sulfate. While reduced/carboxymethylated S protein remained also ineffective in neutralizing other dermatan sulfate compounds with varying degree of sulfation, a synthetic highly basic tridecapeptide, representing a portion of the glycosaminoglycan-binding domain of S protein, counteracted their anticoagulant activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Preissner
K T
KT
Clinical Research Unit for Blood Coagulation and Thrombosis, Max-Planck-Gesellschaft, Justus-Liebig-Universität Giessen, FRG.
Sié
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D000991:Antithrombins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001667:Binding, Competitive; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology*; D006025:Glycosaminoglycans / Q000378:metabolism; D015844:Heparin Cofactor II; D006801:Humans; D017293:Protein S; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000991:Antithrombins; D006023:Glycoproteins; D006025:Glycosaminoglycans; D017293:Protein S; D015844:Heparin Cofactor II; D013917:Thrombin