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Inhibition of plasminogen activator inhibitor-1 binding to endocytosis receptors of the low-density-lipoprotein receptor family by a peptide isolated from a phage display library

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  • Jan Kristian Jensen
  • Anders Malmendal, Danmark
  • Birgit Schiøtt
  • Sune Skeldal, Danmark
  • Katrine E Pedersen, Danmark
  • Leyla Celik, Danmark
  • Niels Chr. Nielsen
  • ,
  • Peter A Andreasen, Danmark
  • Troels Wind, Danmark
  • Molekylærbiologisk Institut
  • Institut for Kemi
  • Interdisciplinary Nanoscience Center
  • Interdisciplinær Nanoscience Forskerskole
The functions of the serpin PAI-1 (plasminogen activator inhibitor-1) are based on molecular interactions with its target proteases uPA and tPA (urokinase-type and tissue-type plasminogen activator respectively), with vitronectin and with endocytosis receptors of the low-density-lipoprotein family. Understanding the significance of these interactions would be facilitated by the ability to block them individually. Using phage display, we have identified the disulfide-constrained peptide motif CFGWC with affinity for natural human PAI-1. The three-dimensional structure of a peptide containing this motif (DVPCFGWCQDA) was determined by liquid-state NMR spectroscopy. A binding site in the so-called flexible joint region of PAI-1 was suggested by molecular modelling and validated through binding studies with various competitors and site-directed mutagenesis of PAI-1. The peptide with an N-terminal biotin inhibited the binding of the uPA-PAI-1 complex to the endocytosis receptors low-density-lipoprotein-receptor-related protein 1A (LRP-1A) and very-low-density-lipoprotein receptor (VLDLR) in vitro and inhibited endocytosis of the uPA-PAI-1 complex in U937 cells. We conclude that the isolated peptide represents a novel approach to pharmacological interference with the functions of PAI-1 based on inhibition of one specific molecular interaction.
TidsskriftBiochemical Journal
Sider (fra-til)387-96
Antal sider10
StatusUdgivet - 1 nov. 2006

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