[Frontiers in Bioscience 14, 1337-1361, January 1, 2009]

Biochemical properties of plasminogen activator inhibitor-1

Daniel Miotto Dupont1,2, Jeppe Buur Madsen1, Thomas Kristensen1, Julie Stove Bodker1, Grant Ellsworth Blouse1, Troels Wind1, Peter Andre Andreasen1

1Department of Molecular Biology and 2Interdisciplinary Nanoscience Center (iNANO), University of Aarhus, Gustav Wieds Vej 10C, 8000 Aarhus C, Denmark

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. General biochemistry of PAI-1
4. Inhibitory properties of PAI-1 and other serpins
5. PAI-1 latency transition
6. PAI-1 - vitronectin binding
7. Global conformational changes of PAI-1 in association with RCL insertion
8. PAI-1 polymerisation
9. Biochemical importance of PAI-1 glycosylation
10. Binding of plasminogen activator - PAI-1 complexes to endocytosis receptors of the low density lipoprotein receptor family
11. Conclusions and perspectives
12. Acknowledgements
13. References

1. ABSTRACT

PAI-1 is a Mr ~50,000 glycoprotein, which is the primary physiological inhibitor of the two plasminogen activators uPA and tPA. PAI-1 belongs to the serpin protein family. Studies of PAI-1 have contributed significantly to the elucidation of the protease inhibitory mechanism of serpins, which is based on a metastable native state becoming stabilised by insertion of the RCL into the central beta-sheet A and formation of covalent complexes with target proteases. In PAI-1, this insertion can occur in the absence of the protease, resulting in generation of a so-called latent, inactive form of the protein. PAI-1, in its active state, also binds to the extracellular protein vitronectin. When in complex with its target proteases, it binds with high affinity to endocytosis receptors of the low density receptor family.