Conformational changes in plasminogen, their effect on activation, and the agents that modulate activation rates - A review

This review was prompted by the increasing volume of observations relating to the modulation of plasminogen activation by a variety of agents of biological significance. Most of these agents accelerate activation by both tissue plasminogen activator (t-PA) and urokinase plasminogen activator (u-PA), but some slow it down. Many of them either modify the apparent affinity of plasminogen to the activators, or the velocity of catalysis, or both, and in some cases they affect the two parameters in seemingly contradictory fashion. In many of the cases the effects are satisfactorily accounted for by stabilization of one or the other of the plasminogen conformations, but often they are due to direct effects on the activators themselves. The effect requires the continued presence of the 'modulator' during activation, which means that catalysis is carried out by a ternary complex consisting of the activator, plasminogen and the modulator. The most significant part of the complex mechanism of modulation appears to be the manipulation - by the modulator - of the conformational state of plasminogen. it is the apparent ease of the conformational transition in plasminogen, to be discussed below, which allows the large variety of structurally diverse molecules to select and stabilize the conformation of their choice and thereby modulate the kinetics of activation. This effect is specific in that it is restricted to the process of activation: in the majority of the cases the modulators have no measurable effect on plasmin action. This does not necessarily mean that they do not interact with plasmin, only that the C-terminal active site region of plasmin is not responsive to events taking place in the N-terminal kringle-rich region of the molecule. A recent review by Ponting et all summarizes the current information on the structure of plasminogen.