The wild-type form of plasminogen activator inhibitor type-2 (PAI-2) and the pathogenic Z-mutant of α1-antitrypsin (α1AT) are serpins that spontaneously polymerize by the loop–sheet mechanism. Compared to the consensus serpin sequence, both PAI-2 and Z-α1AT have deviations in the so-called breach region located at the top of the A β-sheet. In the case of Z-α1AT, conformational perturbations caused by a single amino acid substitution result in polymerization in vivo and predisposes to disease. To test whether the polymerization of PAI-2 is due to aberrations in the breach region, we constructed substitution mutants of PAI-2 with conserved residues in this region. Analysis of the mutants revealed that deviations in the breach region modulate but are not the major cause of PAI-2 polymerization. Rather, PAI-2 exists in a highly polymerogenic conformation and does not require conformational rearrangements before polymerization can take place.
