A redox-sensitive loop regulates plasminogen activator inhibitor type 2 (PAI-2) polymerization.

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

Plasminogen activator inhibitor type 2 (PAI-2) is the only wild-type serpin that polymerizes spontaneously under physiological conditions. We show that PAI-2 loses its ability to polymerize following reduction of thiol groups, suggesting that an intramolecular disulfide bond is essential for the polymerization. A novel disulfide bond was identified between C79 (in the CD-loop) and C161 (at the bottom of helix F). Substitution mutants in which this disulfide bond was broken did not polymerize. Reactive center loop peptide insertion experiments and binding of bis-ANS to hydrophobic cavities indicate that the C79-C161 disulfide bond stabilizes PAI-2 in a polymerogenic conformation with an open A-beta-sheet. Elimination of this disulfide bond causes A-beta-sheet closure and abrogates the polymerization. The finding that cytosolic PAI-2 is mostly monomeric, whereas PAI-2 in the secretory pathway is prone to polymerize, suggests that the redox status of the cell could regulate PAI-2 polymerization. Taken together, our data suggest that the CD-loop functions as a redox-sensitive switch that converts PAI-2 between an active stable monomeric and a polymerogenic conformation, which is prone to form inactive polymers.

Lobov, SergeiUmeå universitet,Institutionen för medicinsk kemi och biofysik (author)
Ohlsson, Per-IngvarUmeå 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)

By the author/editor: Wilczynska, Malg ...; Lobov, Sergei; Ohlsson, Per-Ing ...; Ny, Tor

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