NDLI: Flow induces loop-to-β-hairpin transition on the β-switch of platelet glycoprotein Ibα

Content Provider	PubMed Central
Author	Lou, Jizhong Zhu, Cheng
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.
Related Links	http://dx.doi.org/10.1073/pnas.0801965105
Starting Page	13847
File Format	PDF
ISSN	10916490
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	37
Volume Number	105
Language	English
Publisher	National Academy of Sciences
Publisher Date	2008-09-16
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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