Abstract
Binding of the A1 domain of von Willebrand factor (vWF) to glycoprotein Ibα (GPIbα) results in platelet adhesion, activation, and aggregation that initiates primary hemostasis. Both the elevated shear stress and the mutations associated with type 2B von Willebrand disease enhance the interaction between A1 and GPIbα. Through molecular dynamics simulations for wild-type vWF-A1 and its eight gain of function mutants (R543Q, I546V, ΔSS, etc.), we found that the gain of function mutations destabilize the N-terminal arm, increase a clock pendulum-like movement of the α2-helix, and turn a closed A1 conformation into a partially open one favoring binding to GPIbα. The residue Arg(578) at the α2-helix behaves as a pivot in the destabilization of the N-terminal arm and a consequent dynamic change of the α2-helix. These results suggest a localized dynamics-driven affinity regulation mechanism for vWF-GPIbα interaction. Allosteric drugs controlling this intrinsic protein dynamics may be effective in blocking the GPIb-vWF interaction.
Highlights
Gain of function (GOF) mutations enhance the von Willebrand factor (vWF)-GPIb␣ interaction
GOF Mutation Triggers the Switch from a Stable Conformation to a Localized Unstable One for the A1 Domain—Thermodynamic experiments demonstrated that type 2B mutations destabilize A1 [16]
Less conformational change occurs in the vWF A1 domain, not like the homologous von Willebrand factor A domain, the integrin I domain, whose affinity is regulated by the obvious structural changes caused by a piston and connecting rod-like movement of the C-terminal ␣7-helix [42]
Summary
Gain of function (GOF) mutations enhance the vWF-GPIb␣ interaction. Results: GOF mutations induce destabilization of the N-terminal arm and increase mobility of the ␣2-helix. The residue Arg578 at the ␣2-helix behaves as a pivot in the destabilization of the N-terminal arm and a consequent dynamic change of the ␣2-helix These results suggest a localized dynamics-driven affinity regulation mechanism for vWF-GPIb␣ interaction. A similar increase in binding affinity can be induced in the isolated WT A1 domain by reduction and alkylation of the Cys509– Cys695 disulfide bond and/or by exposure to acidic pH [18, 19] These data suggest that the A1 domain itself may take either a low or a high affinity conformation, and tensile forces and GOF mutations favor the high affinity conformation. The results depict a localized dynamics-driven affinity regulation mechanism for binding of vWF to GPIb␣, provide a novel insight into the structural basis of GOF mutants, and may assist in developing allosteric drugs against the activated A1 domain
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