Flow induces loop-to-beta-hairpin transition on the beta-switch of platelet glycoprotein Ib alpha.
Interaction of glycoprotein Ib alpha (GPIb alpha) with von Willebrand factor (VWF) initiates platelet adhesion to injured vascular wall to stop bleeding. A major contact between GPIb alpha and VWF involves the beta-switch region, which is a loop in the unliganded GPIb alpha but switches to a beta-hairpin in the complex structure. Paradoxically, flow enhances rather than impedes GPIb alpha-VWF binding. Gain-of-function mutations (e.g., M239V) in the beta-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 beta-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 beta-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 beta-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 GPIb alpha via inducing a loop-to-beta-hairpin conformational transition on the beta-switch, thereby promoting VWF binding.
Lou
Jizhong
J
Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA.
Zhu
Cheng
C
D001792:Blood Platelets / Q000737:chemistry* / Q000378:metabolism*; D003198:Computer Simulation; D008024:Ligands; D008958:Models, Molecular; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D014867:Water / Q000737:chemistry
D008024:Ligands; D019038:Platelet Glycoprotein GPIb-IX Complex; D014867:Water
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