Negatively charged organochemical inactivators of the anti-proteolytic activity of plasminogen activator inhibitor-1 (PAI-1) convert it to inactive polymers. As investigated by native gel electrophoresis, the size of the PAI-1 polymers ranged from dimers to multimers of more than 20 units. As compared with native PAI-1, the polymers exhibited an increased resistance to temperature-induced unfolding. Polymerization was associated with specific changes in patterns of digestion with non-target proteases. During incubation with urokinase-type plasminogen activator, the polymers were slowly converted to reactive centre-cleaved monomers, indicating substrate behaviour of the terminal PAI-1 molecules in the polymers. A quadruple mutant of PAI-1 with a retarded rate of latency transition also had a retarded rate of polymerization. Studying a number of serpins by native gel electrophoresis, ligand-induced polymerization was observed only with PAI-1 and heparin cofactor II, which were also able to copolymerize. On the basis of these results, we suggest that the binding of ligands in a specific region of PAI-1 leads to so-called loop–sheet polymerization, in which the reactive centre loop of one molecule binds to β-sheet A in another molecule. Induction of serpin polymerization by small organochemical ligands is a novel finding and is of protein chemical interest in relation to pathological protein polymerization in general.
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June 2003
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Research Article|
June 15 2003
Plasminogen activator inhibitor-1 polymers, induced by inactivating amphipathic organochemical ligands
Katrine E. PEDERSEN;
Katrine E. PEDERSEN
1
∗Department of Molecular Biology, University of Aarhus, Gustav Wieds Vej 10, DK-8000 Aarhus C, Denmark
1To whom correspondence should be addressed (e-mail kep@mb.au.dk).
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Anja P. EINHOLM;
Anja P. EINHOLM
∗Department of Molecular Biology, University of Aarhus, Gustav Wieds Vej 10, DK-8000 Aarhus C, Denmark
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Anni CHRISTENSEN;
Anni CHRISTENSEN
∗Department of Molecular Biology, University of Aarhus, Gustav Wieds Vej 10, DK-8000 Aarhus C, Denmark
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Lotte SCHACK;
Lotte SCHACK
∗Department of Molecular Biology, University of Aarhus, Gustav Wieds Vej 10, DK-8000 Aarhus C, Denmark
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Troels WIND;
Troels WIND
∗Department of Molecular Biology, University of Aarhus, Gustav Wieds Vej 10, DK-8000 Aarhus C, Denmark
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John M. KENNEY;
John M. KENNEY
†Institute for Storage Ring Facilities, University of Aarhus, Ny Munkegade 525, DK-8000 Aarhus C, Denmark
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Peter A. ANDREASEN
Peter A. ANDREASEN
∗Department of Molecular Biology, University of Aarhus, Gustav Wieds Vej 10, DK-8000 Aarhus C, Denmark
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Publisher: Portland Press Ltd
Received:
December 02 2002
Revision Received:
March 24 2003
Accepted:
March 26 2003
Accepted Manuscript online:
March 26 2003
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2003
2003
Biochem J (2003) 372 (3): 747–755.
Article history
Received:
December 02 2002
Revision Received:
March 24 2003
Accepted:
March 26 2003
Accepted Manuscript online:
March 26 2003
Citation
Katrine E. PEDERSEN, Anja P. EINHOLM, Anni CHRISTENSEN, Lotte SCHACK, Troels WIND, John M. KENNEY, Peter A. ANDREASEN; Plasminogen activator inhibitor-1 polymers, induced by inactivating amphipathic organochemical ligands. Biochem J 15 June 2003; 372 (3): 747–755. doi: https://doi.org/10.1042/bj20021868
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