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 rela ting to the modulation of plasminogen activation by a variety of agent s of biological significance. Most of these agents accelerate activati on by both tissue plasminogen activator (t-PA) and urokinase plasminog en activator (u-PA), but some slow it down. Many of them either modify the apparent affinity of plasminogen to the activators, or the veloci ty of catalysis, or both, and in some cases they affect the two parame ters in seemingly contradictory fashion. In many of the cases the effe cts are satisfactorily accounted for by stabilization of one or the ot her of the plasminogen conformations, but often they are due to direct effects on the activators themselves. The effect requires the continu ed presence of the 'modulator' during activation, which means that cat alysis is carried out by a ternary complex consisting of the activator , plasminogen and the modulator. The most significant part of the comp lex mechanism of modulation appears to be the manipulation - by the mo dulator - of the conformational state of plasminogen. it is the appare nt ease of the conformational transition in plasminogen, to be discuss ed below, which allows the large variety of structurally diverse molec ules to select and stabilize the conformation of their choice and ther eby modulate the kinetics of activation. This effect is specific in th at it is restricted to the process of activation: in the majority of t he cases the modulators have no measurable effect on plasmin action. T his does not necessarily mean that they do not interact with plasmin, only that the C-terminal active site region of plasmin is not responsi ve to events taking place in the N-terminal kringle-rich region of the molecule. A recent review by Ponting et all summarizes the current in formation on the structure of plasminogen.