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Thromb Haemost 2003; 90(01): 52-58
DOI: 10.1055/s-0037-1613598
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Elucidation of the epitope of a latency-inducing antibody: identification of a new molecular target for PAI-1 inhibition

Dominik Naessens
1   Laboratory for Pharmaceutical Biology and Phytopharmacology, Faculty of Pharmaceutical Sciences, K. U. Leuven, Belgium
,
Ann Gils
1   Laboratory for Pharmaceutical Biology and Phytopharmacology, Faculty of Pharmaceutical Sciences, K. U. Leuven, Belgium
,
Griet Compernolle
1   Laboratory for Pharmaceutical Biology and Phytopharmacology, Faculty of Pharmaceutical Sciences, K. U. Leuven, Belgium
,
Paul J. Declerck
1   Laboratory for Pharmaceutical Biology and Phytopharmacology, Faculty of Pharmaceutical Sciences, K. U. Leuven, Belgium
› Author AffiliationsFinancial support: This study was supported in part by the Research Fund KULeuven (OT/02/55) and the Fund for Scientific Research (FWO-Vlaanderen, G.0225.01). A.G. is a postdoctoral fellow of the Fund for Scientific Research (F.W.O.-Vlaanderen).
Further Information

Publication History

Received 04 March 2003

Accepted after revision 03 April 2003

Publication Date:
07 December 2017 (online)

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Summary

The monoclonal antibody MA-33B8, directed against the serpin plasminogen activator inhibitor-1 (PAI-1), has unique functional properties as it induces acceleration of the active-to-latent transition (Verhamme I et al. J Biol Chem 274: 17511-7, 1999), resulting in PAI-1 activity neutralization. In this study, we have identified Lys88, Asp89, Lys176 and His229 as the major residues of the conformational epitope. Lysine88 and aspartic acid89, contributing the most, are located on the loop between α-helix D and β-strand 2A. Strikingly, these residues undergo dramatic conformational changes during latency conversion. The three-dimensional localization of this epitope and its differential exposure in active and latent forms of PAI-1 provide a molecular explanation for the underlying mechanism of MA-33B8. Rearrangements of hydrogen bonds in this region upon latency transition, strongly suggest that binding of MA-33B8 may result in the generation of energy required in the rate-limiting step of latency transition. Thus, this novel epitope reveals a new interaction site in PAI-1 as a putative molecular target to modulate PAI-1 activity.

Keywords

PAI-1 - fibrinolysis - epitope mapping - monoclonal antibody
 

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