Flow induces loop-to-β-hairpin transition on the β-switch of platelet glycoprotein Ibα
- 16 September 2008
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 105 (37), 13847-13852
- https://doi.org/10.1073/pnas.0801965105
Abstract
Interaction of glycoprotein Ibα (GPIbα) with von Willebrand factor (VWF) initiates platelet adhesion to injured vascular wall to stop bleeding. A major contact between GPIbα and VWF involves the β-switch region, which is a loop in the unliganded GPIbα but switches to a β-hairpin in the complex structure. Paradoxically, flow enhances rather than impedes GPIbα-VWF binding. Gain-of-function mutations (e.g., M239V) in the β-switch reduce the flow requirement for VWF binding, whereas loss-of-function mutations (e.g., A238V) increase the flow requirement. These phenomena cannot be explained by crystal structures or energy calculations. Herein we demonstrate that the β-hairpin is unstable without contacting VWF, in that it switches to a loop in free molecular dynamics simulations. Simulations with a novel flow molecular dynamics algorithm show that the loop conformation is unstable in the presence of flow, as it switches to β-hairpin even without contacting VWF. Compared with the wild-type, it is easier for the M239V mutant but harder for the A238V mutant to switch to β-hairpin in the presence of flow. These results elucidate the structural basis for the two mutants and suggest a regulatory mechanism by which flow activates GPIbα via inducing a loop-to-β-hairpin conformational transition on the β-switch, thereby promoting VWF binding.Keywords
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