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The Reactive-center Loop of Active PAI-1 is Folded Close to the Protein Core and can be Partially Inserted
Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
Faculty of Science and Technology, Chemistry.
Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
Faculty of Science and Technology, Chemistry.
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2004 (English)In: Journal of Molecular Biology, Vol. 335, no 3, 823-32 p.Article in journal (Refereed) Published
Abstract [en]

Plasminogen activator inhibitor 1 (PAI-1) is the main inhibitor of plasminogen activators and plays an important role in many pathophysiological processes. Like other members of the serpin family, PAI-1 has a reactive center consisting of a mobile loop (RCL) with P1 and P1′ residues acting as a “bait” for cognate protease. In contrast to the other serpins, PAI-1 loses activity by spontaneous conversion to an inactive latent form. This involves full insertion of the RCL into β-sheet A. To search for molecular determinants that could be responsible for conversion of PAI-1 to the latent form, we studied the conformation of the RCL in active PAI-1 in solution. Intramolecular distance measurements by donor–donor energy migration and probe quenching methods reveal that the RCL is located much closer to the core of PAI-1 than has been suggested by the recently resolved X-ray structures of stable PAI-1 mutants. Disulfide bonds can be formed in double-cysteine mutants with substitutions at positions P11 or P13 of the RCL and neighboring residues in β-sheet A. This suggests that the RCL may be preinserted up to residue P13 in active PAI-1, and possibly even to residue P11. We propose that the close proximity of the RCL to the protein core, and the ability of the loop to preinsert into β-sheet A is a possible reason for PAI-1 being able to convert spontaneously to its latent form.

Place, publisher, year, edition, pages
2004. Vol. 335, no 3, 823-32 p.
Keyword [en]
fluorescence, donor–donor energy migration, distance measurement, serpin, PAI-1
URN: urn:nbn:se:umu:diva-14769DOI: doi:10.1016/j.jmb.2003.11.005OAI: diva2:154441
Available from: 2007-06-26 Created: 2007-06-26 Last updated: 2011-01-12Bibliographically approved

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Wilczynska, MalgorzataJohansson, Lennart B-ÅNy, Tor
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