The spontaneous polymerization of plasminogen activator inhibitor type-2 and Z-antitrypsin are due to different molecular aberrations

Wilczynska, MalgorzataUmeå universitet,Institutionen för medicinsk kemi och biofysik (author)

The wild-type form of plasminogen activator inhibitor type-2 (PAI-2) and the pathogenic Z-mutant of alpha(1)-antitrypsin (alpha(1)AT) are serpins that spontaneously polymerize by the loop-sheet mechanism. Compared to the consensus serpin sequence, both PAI-2 and Z-alpha(1)AT have deviations in the so-called breach region located at the top of the A beta-sheet. In the case of Z-alpha(1)AT, 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.

Lobov, SergeiUmeå universitet,Institutionen för medicinsk kemi och biofysik (author)
Ny, TorUmeå universitet,Institutionen för medicinsk kemi och biofysik(Swepub:umu)tony0001 (author)
Umeå universitetInstitutionen för medicinsk kemi och biofysik (creator_code:org_t)

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