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How vitronectin binds PAI-1 to modulate fibrinolysis and cell migration

Nature Structural & Molecular Biology volume 10, pages 541–544 (2003)Cite this article

Abstract

The interaction of the plasma protein vitronectin with plasminogen activator inhibitor-1 (PAI-1) is central to human health. Vitronectin binding extends the lifetime of active PAI-1, which controls hemostasis by inhibiting fibrinolysis and has also been implicated in angiogenesis. The PAI-1–vitronectin binding interaction also affects cell adhesion and motility. For these reasons, elevated PAI-1 activities are associated both with coronary thrombosis and with a poor prognosis in many cancers. Here we show the crystal structure at a resolution of 2.3 Å of the complex of the somatomedin B domain of vitronectin with PAI-1. The structure of the complex explains how vitronectin binds to and stabilizes the active conformation of PAI-1. It also explains the tissue effects of PAI-1, as PAI-1 competes for and sterically blocks the interaction of vitronectin with cell surface receptors and integrins. Structural understanding of the essential biological roles of the interaction between PAI-1 and vitronectin opens the prospect of specifically designed blocking agents for the prevention of thrombosis and treatment of cancer.

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Figure 1: Ribbon diagrams of the complex and its components.
Figure 2: Stereo view of interacting residues in the PAI-1–SMB interface.

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Acknowledgements

We thank N. Duke for assistance in collecting data at the APS and A. McCoy for advice on fitting the somatomedin B domain to the initial electron density maps. H. Ogawa kindly provided cDNA for vitronectin. Use of the SBC beamline at the APS was supported by the US Department of Energy Office of Biological and Environmental Research. Beamtime at station 14.2 of Daresbury SRS was provided by CLRC Daresbury Laboratory. R.J.R. and R.W.C. were supported by the Wellcome Trust (UK) and J.A.H. by the Medical Research Council (UK) and National Institutes of Health (USA).

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  1. Navraj S Pannu

    Present address: Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, 2300 RA, Leiden, The Netherlands

Authors and Affiliations

  1. Department of Haematology, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Hills Road, Cambridge, CB2 2XY, UK

    Aiwu Zhou, James A Huntington, Navraj S Pannu, Robin W Carrell & Randy J Read

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Correspondence to Randy J Read.

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Zhou, A., Huntington, J., Pannu, N. et al. How vitronectin binds PAI-1 to modulate fibrinolysis and cell migration. Nat Struct Mol Biol 10, 541–544 (2003). https://doi.org/10.1038/nsb943

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