Role of protein conformational changes, surface approximation and protein cofactors in heparin-accelerated antithrombin-proteinase reactions.

Abstract

Antithrombin functions as the principal plasma protein inhibitor of most blood coagulation proteinases.1,2 The essential role of this inhibitor in regulating the activity of these proteinases in vivo is indicated from the well-established link between inherited or acquired deficiencies of antithrombin and the tendency to develop thrombotic disease. Antithrombin is a member of the serpin superfamily of protein proteinase inhibitors and its main target enzymes include the blood coagulation factors IXa, Xa and thrombin. This and other serpins are distinguished from other family members in that their reactions with target enzymes are greatly accelerated by the binding of heparin or heparan sulfate glycosaminoglycans. This property is chiefly responsible for the anticoagulant activity of heparin and has suggested a role for endogenous heparin and heparan sulfate in the regulation of blood coagulation proteinases by antithrombin. In this article, we will review our present understanding of the relationship between antithrombin structure and function based on currently available evidence. Our discussion will focus principally on two areas: 1) the mechanism by which antithrombin and other serpins inhibit their target proteinases; and 2) the molecular basis of heparin’s accelerating effect on antithrombin-proteinase reactions.