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DOI: 10.1055/s-0037-1613200
Importance of N-Terminal Residues in Plasminogen Activator Inhibitor 1 on its Antibody Induced Latency Transition
Publikationsverlauf
Received
30. Januar 2002
Accepted after revision
22. April 2002
Publikationsdatum:
07. Dezember 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/200202/lookinside/thumbnails/10-1055-s-0037-1613200-1.jpg)
Summary
The serpin plasminogen activator inhibitor-1 (PAI-1) is a wellknown risk factor for thromboembolic and cardiovascular diseases. Many efforts have been made to reveal structure-function relationship in PAI-1, including the understanding of its unique latency transition. In this study, we describe the molecular characterization of PAI-1 neutralization by MA-159M12, a monoclonal antibody against rat PAI-1.
Time-dependent inactivation of PAI-1, exposure of a trypsin cleavage site typically for the latent conformation and disappearance of elastase susceptibility revealed that MA-159M12 accelerated the active to latent, conformational transition (t1/2 120 ± 12 min and 18 ± 3.6 min in the absence and presence of MA-159M12, p <0.0001).
Cross-reactivity analysis of the antibody with various rat/human PAI-1 chimeras revealed that the epitope resides in αhA of rat PAI-1. Subsequent alanine-scanning mutagenesis and binding studies demonstrated that Pro2- Leu3- Pro4-Glu5 constitute the major residues of the epitope for MA-159M12. In conclusion, these findings demonstrate that, even though unexpected based on current knowledge on PAI-1 stability and function, interference with αhA results in a destabilisation of its active, inhibitory conformation. Therefore, αhA forms a putative target for the rational development of PAI-1 neutralizing components.
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