期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2008
卷号：105
期号：37
页码：13847-13852
DOI：10.1073/pnas.0801965105
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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.
关键词：flow molecular dynamics ; Platelet-type von Willebrand disease ; von Willebrand factor ; conformational change ; mechanical sensing
