STRUCTURE–FUNCTION RELATIONSHIP IN THE PLASMINOGEN ACTIVATOR ISOLATED FROM THE VENOM OF TRIMERESURUS STEJNEGERI

Abstract

Snake toxins impede hemostasis of prey through multiple mechanisms. Blood coagulation factors V and X, prothrombin, or the anticoagulant protein C are among their typical targets. A number of thrombin-like and plasmin-like (fibrinolytic) enzymes have also been characterized that interact with fibrin or fibrinogen. To date, however, only three direct plasminogen activators have been described in snake venom. This review updates our current knowledge on the structure–function relationship of these activators. The mechanism of plasminogen activation by toxins is outlined and compared with that of their mammalian counterparts (tissue plasminogen activator and urokinase, as well as plasminogen activator isolated from saliva of the common vampire bat). Plasmin produced through plasminogen activation is a fairly efficient protease of broad specificity. Uncontrolled plasmin degrades fibrinogen and components of the extracellular matrix in addition to fibrin. At least three mechanisms normally constrain and localize plasmin production as well as activity. First, plasminogen activator binds fibrin or a cell receptor localizing plasmin production. Second, when fibrin degradation products start to disseminate, a powerful inhibitor neutralizes the bound activator. Likewise, two powerful inhibitors also knock out plasmin when it starts to disseminate in blood. Thus, plasmin normally operates only in the vicinity of a fibrin clot, where inhibitors are locally depleted and massive plasminogen activation can take place. Snake venom plasminogen activators escape such confinement. Through site-directed mutagenesis and x-ray diffraction studies, part of the molecular basis allowing invulnerability of these toxins has been decrypted. This review highlights the role of specific areas and distinct amino acids involved in their activity.