Regions remote from the site of cleavage determine macromolecular substrate recognition by the prothrombinase complex.

The Journal of Biological Chemistry
A Betz, S Krishnaswamy

Abstract

The proteolytic formation of thrombin is catalyzed by the prothrombinase complex of blood coagulation. The kinetics of prethrombin 2 cleavage was studied to delineate macromolecular substrate structures necessary for recognition at the exosite(s) of prothrombinase. The product, alpha-thrombin, was a linear competitive inhibitor of prethrombin 2 activation without significantly inhibiting peptidyl substrate cleavage by prothrombinase. Prethrombin 2 and alpha-thrombin compete for binding to the exosite without restricting access to the active site of factor Xa within prothrombinase. Inhibition by alpha-thrombin was not altered by saturating concentrations of low molecular weight heparin. Furthermore, proteolytic removal of the fibrinogen recognition site in alpha-thrombin only had a modest effect on its inhibitory properties. Both alpha-thrombin and prethrombin 2 were cleaved with chymotrypsin at Trp148 and separated into component domains. The C-terminal-derived zeta2 fragment retained the ability to selectively inhibit macromolecular substrate cleavage by prothrombinase, while the zeta1 fragment was without effect. As the zeta2 fragment lacks the fibrinogen recognition site, the P1-P3 residues or the intact cleavage site, speci...Continue Reading

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Citations

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