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A redox-sensitive l...
A redox-sensitive loop regulates plasminogen activator inhibitor type 2 (PAI-2) polymerization.
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- Wilczynska, Malgorzata (author)
- Umeå universitet,Institutionen för medicinsk kemi och biofysik
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- Lobov, Sergei (author)
- Umeå universitet,Institutionen för medicinsk kemi och biofysik
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- Ohlsson, Per-Ingvar (author)
- Umeå universitet,Institutionen för medicinsk kemi och biofysik
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- Ny, Tor (author)
- Umeå universitet,Institutionen för medicinsk kemi och biofysik
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(creator_code:org_t)
- Wiley, 2003
- 2003
- English.
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In: EMBO Journal. - : Wiley. - 0261-4189 .- 1460-2075. ; 22:8, s. 1753-1761
- Related links:
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https://europepmc.or...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Subject headings
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- 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.
Keyword
- PAI-2
- polymerization
- redox
- serpin
- MEDICINE
- MEDICIN
Publication and Content Type
- ref (subject category)
- art (subject category)
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