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Research ArticleArticle

A Peptide Accelerating the Conversion of Plasminogen Activator Inhibitor-1 to an Inactive Latent State

Lisa Mathiasen, Daniel M. Dupont, Anni Christensen, Grant E. Blouse, Jan K. Jensen, Ann Gils, Paul J. Declerck, Troels Wind and Peter A. Andreasen
Molecular Pharmacology September 2008, 74 (3) 641-653; DOI: https://doi.org/10.1124/mol.108.046417
Lisa Mathiasen
Department of Molecular Biology, Aarhus University, Denmark (L.M., D.M.D., A.C., G.E.B., J.K.J., T.W., P.A.A.); and Laboratory for Pharmaceutical Biology, Faculty of Pharmaceutical Sciences, Katholieke Universiteit, Leuven, Belgium (A.G., P.J.D.)
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Daniel M. Dupont
Department of Molecular Biology, Aarhus University, Denmark (L.M., D.M.D., A.C., G.E.B., J.K.J., T.W., P.A.A.); and Laboratory for Pharmaceutical Biology, Faculty of Pharmaceutical Sciences, Katholieke Universiteit, Leuven, Belgium (A.G., P.J.D.)
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Anni Christensen
Department of Molecular Biology, Aarhus University, Denmark (L.M., D.M.D., A.C., G.E.B., J.K.J., T.W., P.A.A.); and Laboratory for Pharmaceutical Biology, Faculty of Pharmaceutical Sciences, Katholieke Universiteit, Leuven, Belgium (A.G., P.J.D.)
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Grant E. Blouse
Department of Molecular Biology, Aarhus University, Denmark (L.M., D.M.D., A.C., G.E.B., J.K.J., T.W., P.A.A.); and Laboratory for Pharmaceutical Biology, Faculty of Pharmaceutical Sciences, Katholieke Universiteit, Leuven, Belgium (A.G., P.J.D.)
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Jan K. Jensen
Department of Molecular Biology, Aarhus University, Denmark (L.M., D.M.D., A.C., G.E.B., J.K.J., T.W., P.A.A.); and Laboratory for Pharmaceutical Biology, Faculty of Pharmaceutical Sciences, Katholieke Universiteit, Leuven, Belgium (A.G., P.J.D.)
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Ann Gils
Department of Molecular Biology, Aarhus University, Denmark (L.M., D.M.D., A.C., G.E.B., J.K.J., T.W., P.A.A.); and Laboratory for Pharmaceutical Biology, Faculty of Pharmaceutical Sciences, Katholieke Universiteit, Leuven, Belgium (A.G., P.J.D.)
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Paul J. Declerck
Department of Molecular Biology, Aarhus University, Denmark (L.M., D.M.D., A.C., G.E.B., J.K.J., T.W., P.A.A.); and Laboratory for Pharmaceutical Biology, Faculty of Pharmaceutical Sciences, Katholieke Universiteit, Leuven, Belgium (A.G., P.J.D.)
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Troels Wind
Department of Molecular Biology, Aarhus University, Denmark (L.M., D.M.D., A.C., G.E.B., J.K.J., T.W., P.A.A.); and Laboratory for Pharmaceutical Biology, Faculty of Pharmaceutical Sciences, Katholieke Universiteit, Leuven, Belgium (A.G., P.J.D.)
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Peter A. Andreasen
Department of Molecular Biology, Aarhus University, Denmark (L.M., D.M.D., A.C., G.E.B., J.K.J., T.W., P.A.A.); and Laboratory for Pharmaceutical Biology, Faculty of Pharmaceutical Sciences, Katholieke Universiteit, Leuven, Belgium (A.G., P.J.D.)
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Abstract

The serpin plasminogen activator inhibitor-1 (PAI-1) is a specific inhibitor of plasminogen activators and a potential therapeutic target in cancer and cardiovascular diseases. Accordingly, formation of a basis for development of specific PAI-1-inactivating agents is of great interest. One possible inactivation mode for PAI-1 is conversion to the inactive, so-called latent state. We have now screened a phage-displayed peptide library with PAI-1 as bait and isolated a 31-residue cysteine-rich peptide that will be referred to as paionin-4. A recombinant protein consisting of paionin-4 fused to domains 1 and 2 of the phage coat protein g3p caused a 2- to 3-fold increase in the rate of spontaneous inactivation of PAI-1. Paionin-4-D1D2 bound PAI-1 with a KD in the high nanomolar range. Using several biochemical and biophysical methods, we demonstrate that paionin-4-D1D2-stimulated inactivation consists of an acceleration of conversion to the latent state. As demonstrated by site-directed mutagenesis and competition with other PAI-1 ligands, the binding site for paionin-4 was localized in the loop between α-helix D and β-strand 2A. We also demonstrate that a latency-inducing monoclonal antibody has an overlapping, but not identical binding site, and accelerates latency transition by another mechanism. Our results show that paionin-4 inactivates PAI-1 by a mechanism clearly different from other peptides, small organochemical compounds, or antibodies, whether they cause inactivation by stimulating latency transition or by other mechanisms, and that the loop between α-helix D and β-strand 2A can be a target for PAI-1 inactivation by different types of compounds.

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Molecular Pharmacology: 74 (3)
Molecular Pharmacology
Vol. 74, Issue 3
1 Sep 2008
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Research ArticleArticle

A Peptide Accelerating the Conversion of Plasminogen Activator Inhibitor-1 to an Inactive Latent State

Lisa Mathiasen, Daniel M. Dupont, Anni Christensen, Grant E. Blouse, Jan K. Jensen, Ann Gils, Paul J. Declerck, Troels Wind and Peter A. Andreasen
Molecular Pharmacology September 1, 2008, 74 (3) 641-653; DOI: https://doi.org/10.1124/mol.108.046417

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Research ArticleArticle

A Peptide Accelerating the Conversion of Plasminogen Activator Inhibitor-1 to an Inactive Latent State

Lisa Mathiasen, Daniel M. Dupont, Anni Christensen, Grant E. Blouse, Jan K. Jensen, Ann Gils, Paul J. Declerck, Troels Wind and Peter A. Andreasen
Molecular Pharmacology September 1, 2008, 74 (3) 641-653; DOI: https://doi.org/10.1124/mol.108.046417
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