Polymerization of plasminogen activator inhibitor-1

The activity of the serine proteinase inhibitor (serpin) plasminogen activa tor inhibitor-1 (PAI-1) is controlled by the intramolecular incorporation o f the reactive loop into beta -sheet A with the generation of an inactive l atent species. Other members of the serpin superfamily can be pathologicall y inactivated by intermolecular linkage between the reactive loop of one mo lecule and beta -sheet A of a second to form chains of polymers associated with diverse diseases. It has long been believed that PAI-1 is unique among active serpins in that it does not form polymers. We show here that recomb inant native and latent PAI-1 spontaneously form polymers in vitro at low p H although with distinctly different electrophoretic patterns of polymeriza tion. The polymers of both the native and latent species differ from the ty pical loop-A-sheet polymers of other serpins in that they readily dissociat e back to their original monomeric form. The findings with PAI-1 are compat ible with different mechanisms of linkage, each involving beta -strand addi tion of the reactive loop to s7A in native PAI-1 and to s1C in latent PAI-1 . Glycosylated native and latent PAI-1 can also form polymers under similar conditions, which may be of in vivo importance in the low pH environment o f the platelet.