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

J.K. Jensen, A. Malmendal, B. Schiøtt, S. Skeldal, K.E. Pedersen, L. Celik, N.Chr. Nielsen, P.A. Andreasen, T. Wind*

*Corresponding author

Publikation: Bidrag til tidsskriftTidsskriftartikelpeer review


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. textcopyright 2006 Biochemical Society.
TidsskriftBiochemical Journal
Udgave nummer3
Sider (fra-til)387–396
StatusUdgivet - 2006
Udgivet eksterntJa

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  • Endocytosis
  • Ligand docking
  • Lipoprotein receptor
  • Phage display
  • Plasminogen activator inhibitor-1 (PAI-1)
  • Vitronectin

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