DEFINING THE HEPARIN-BINDING DOMAIN OF ANTITHROMBIN

Antithrombin is a serine protease inhibitor that participates in the inactivation and removal from the circulation of thrombin and a variety of other procoagulant serine proteases. Antithrombin is also the major plasma cofactor of heparin which exerts its therapeutic effect primarily through its ability to substantially increase the rate of inactivation by antithrombin of the procoagulant serine proteases. Binding of heparin to antithrombin is thus believed to be a prerequisite for this rate enhancement effect. Heparin binding to antithrombin is mediated by a well-defined unique heparin pentasaccharide sequence. Interaction between this pentasaccharide sequence and antithrombin induces a conformational change in antithrombin, an alteration that appears to be sufficient to explain the enhanced ability of antithrombin to inhibit factor Xa and related serine proteases, but not thrombin. Heparin species with longer polysaccharide chains appear to be required in order to enhance the inhibition of thrombin by antithrombin. This may be because the enhancement of this reaction requires that heparin interacts simultaneously with both the antithrombin and the thrombin molecules. This review describes the interactions between heparin and antithrombin, focusing on the antithrombin residues which are involved in the binding of heparin. The role of the heparin-induced conformational change in enhancing serine protease inhibition by antithrombin is also explored. Then, based on available data, an hypothesis is proposed to explain the mechanisms by which heparin accelerates the rate of inactivation by antithrombin of the various serine proteases.