Title: Importance of N-terminal residues in plasminogen activator inhibitor 1 on its antibody induced latency transition
Authors: Ngo, Thu-Hoa
Zhou, Yan
Stassen, Jean-Marie
Declerck, Paul # ×
Issue Date: Aug-2002
Series Title: Thrombosis and haemostasis vol:88 issue:2 pages:288-93
Abstract: The serpin plasminogen activator inhibitor-1 (PAI-1) is a well-known 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 alpha hA 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 alpha hA results in a destabilisation of its active, inhibitory conformation. Therefore, alpha hA forms a putative target for the rational development of PAI-1 neutralizing components.
ISSN: 0340-6245
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory for Pharmaceutical Biology (-)
× corresponding author
# (joint) last author

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