A template-assembled synthetic protein surface mimetic of the von Willebrand factor A1 domain inhibits botrocetin-induced platelet aggregation.

Détails

ID Serval
serval:BIB_87B27414B1B6
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
A template-assembled synthetic protein surface mimetic of the von Willebrand factor A1 domain inhibits botrocetin-induced platelet aggregation.
Périodique
Chembiochem
Auteur⸱e⸱s
Hauert J., Fernandez-Carneado J., Michielin O., Mathieu S., Grell D., Schapira M., Spertini O., Mutter M., Tuchscherer G., Kovacsovics T.
ISSN
1439-4227
Statut éditorial
Publié
Date de publication
2004
Peer-reviewed
Oui
Volume
5
Numéro
6
Pages
856-864
Langue
anglais
Notes
Publication types: Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
Platelet adhesion, the initial step of platelet activation, is mediated by the interaction of von Willebrand factor (VWF) with its platelet receptor, the GPIb-IX complex. The binding of VWF to GPIb-IX is induced either by increased shear stress or by exogenous modulators, such as botrocetin. At a molecular level, this interaction takes place between the A1 domain of VWF and the GPIb alpha chain of the GPIb-IX complex. We report here the design and functional characteristics of a VWF template-assembled synthetic protein (TASP), a chimeric four-helix-bundle TASP scaffold mimicking the surface of the A1 domain. Twelve residues located on helices alpha 3 and alpha 4 in the native A1 domain were grafted onto a surface formed by two neighboring helices of the TASP. VWF TASP was found to inhibit specifically botrocetin-induced platelet aggregation and to bind both botrocetin and GPIb alpha. However, in contrast to the native A1 domain, VWF TASP did not bind simultaneously to both ligands. Modeling studies revealed that the relative orientation of the alpha helices in VWF TASP led to a clash of bound botrocetin and GPIb alpha. These results demonstrate that a chimeric four-helix-bundle TASP as a scaffold offers a suitable surface for presenting crucial residues of the VWF A1 domain; the potential of the TASP approach for de novo protein design and mimicry is thereby illustrated.
Mots-clé
Binding Sites, Biomimetic Materials/chemistry, Circular Dichroism, Crotalid Venoms/antagonists &amp, inhibitors, Crotalid Venoms/pharmacology, Humans, Models, Molecular, Platelet Adhesiveness/physiology, Platelet Aggregation Inhibitors/pharmacology, Platelet Glycoprotein GPIb-IX Complex/metabolism, Protein Engineering, Receptors, Platelet-Derived Growth Factor/metabolism, Templates, Genetic, von Willebrand Factor/chemistry, von Willebrand Factor/genetics
Pubmed
Web of science
Création de la notice
28/01/2008 12:22
Dernière modification de la notice
16/06/2021 6:36
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