Premium
A Template‐Assembled Synthetic Protein Surface Mimetic of the von Willebrand Factor A1 domain Inhibits Botrocetin‐Induced Platelet Aggregation
Author(s) -
Hauert Jacques,
FernandezCarneado Jimena,
Michielin Olivier,
Mathieu Stéphane,
Grell Daniel,
Schapira Marc,
Spertini Olivier,
Mutter Manfred,
Tuchscherer Gabriele,
Kovacsovics Tibor
Publication year - 2004
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.200300826
Subject(s) - von willebrand factor , chemistry , platelet activation , biophysics , platelet , platelet glycoprotein gpib ix complex , glycoprotein ib , helix (gastropod) , biochemistry , platelet membrane glycoprotein , stereochemistry , biology , receptor , immunology , ecology , snail
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 GPIbα 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 α3 and α4 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 GPIbα. 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 α helices in VWF TASP led to a clash of bound botrocetin and GPIbα. 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.