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Structural Bases of the Redox-dependent Conformational Switch in the Serpin PAI-2
Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
Faculty of Science and Technology, Chemistry.
Faculty of Science and Technology, Chemistry.
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2004 (English)In: Journal of Molecular Biology, Vol. 344, no 5, 1359-68 p.Article in journal (Refereed) Published
Abstract [en]

Depending on the redox-status, the serpin plasminogen activator inhibitor type 2 (PAI-2) can exist in either a stable monomeric or polymerogenic form. The latter form, which spontaneously forms loop-sheet polymers, has an open β-sheet A and is stabilized by a disulfide bond between C79 (in the CD-loop) and C161 (at the bottom of PAI-2). Reduction of this bond results in a closing of the β-sheet A and converts PAI-2 to a stable monomeric form. Here we show that the stable monomeric and polymerogenic forms of PAI-2 are fully interconvertible, depending on redox-status of the environment. Our intramolecular distance measurements indicate that the CD-loop folds mainly on one side of the stable monomeric form of the inhibitor. However, the loop can translocate about 54 Å to the bottom of PAI-2 so that the C79–C161 disulfide bond can form under oxidizing conditions. We show also that the redox-active C79 can form a disulfide-link to the matrix protein vitronectin, suggesting that vitronectin can stabilize active PAI-2 in extracellular compartments. PAI-2 is therefore a rare example of a redox-sensitive protein for which the activity and polymerization ability are regulated by reversible disulfide bond formation leading to major translocation of a loop and significant conformational changes in the molecule.

Place, publisher, year, edition, pages
2004. Vol. 344, no 5, 1359-68 p.
Keyword [en]
PAI-2, redox, serpin, vitronectin, homo-transfer
Identifiers
URN: urn:nbn:se:umu:diva-14771DOI: doi:10.1016/j.jmb.2004.10.010OAI: oai:DiVA.org:umu-14771DiVA: diva2:154443
Available from: 2007-06-26 Created: 2007-06-26 Last updated: 2011-01-12Bibliographically approved

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CiteExportLink to record
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Citation style
  • apa
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