A redox-sensitive loop regulates plasminogen activator inhibitor type 2 (PAI-2) polymerization.
2003 (English)In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 22, no 8, 1753-1761 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2003. Vol. 22, no 8, 1753-1761 p.
PAI-2, polymerization, redox, serpin
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:umu:diva-3837DOI: 10.1093/emboj/cdg178PubMedID: 12682008OAI: oai:DiVA.org:umu-3837DiVA: diva2:142718