Structure and function of plasminogen activator inhibitor-2

Serine proteinase inhibitors (serpins) are well known regulators of extracellular proteolytic pathways. A recently identified group of intracellular serpins of mammalian and viral origin, designated ovalbumine-like serpins, modify intracellular proteolytic pathways involved in the regulation of apoptosis and inflammation. This review focuses on plasminogen activator inhibitor-2 (PAI-2) in terms of the molecular structure-function relationships and its intracellular functions, in particular in relation to apoptosis. PAI-2 inhibits apoptosis in cell lines challenged with tumor necrosis factor or certain viruses. The intracellular proteinases which PAI-2 act upon are still unknown. During myeloid apoptosis, PAI-2 proteolytically modified to a smaller but still proteinase inhibitory form. PAI-2 is unique among the serpins with respect to its large CD-domain localized between alpha-helices C and D. Recent data show that two domains in PAI-2 are required for its antiapoptotic activity, the CD-domain and the proteinase reactive site. We have shown the CD-domain is involved in covalent and reversible interactions with cytosolic proteins, e.g. the annexins. These intracellular PAI-2-reactive proteins might represent participants in signalling pathways involved in the regulation of cell survival.