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A mechanism for localized dynamics-driven affinity regulation of the binding of von Willebrand factor to platelet glycoprotein Ib?.

ABSTRACT: Binding of the A1 domain of von Willebrand factor (vWF) to glycoprotein Ib? (GPIb?) 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 GPIb?. Through molecular dynamics simulations for wild-type vWF-A1 and its eight gain of function mutants (R543Q, I546V, ?SS, etc.), we found that the gain of function mutations destabilize the N-terminal arm, increase a clock pendulum-like movement of the ?2-helix, and turn a closed A1 conformation into a partially open one favoring binding to GPIb?. The residue Arg(578) 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. Allosteric drugs controlling this intrinsic protein dynamics may be effective in blocking the GPIb-vWF interaction.

SUBMITTER: Liu G

PROVIDER: S-EPMC3772212 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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A mechanism for localized dynamics-driven affinity regulation of the binding of von Willebrand factor to platelet glycoprotein Ibα.

Liu Guangjian G Fang Ying Y Wu Jianhua J

The Journal of biological chemistry 20130731 37

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 destabiliz ...[more]

PMID: 23902764

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Project description:Essentials von Willebrand factor (VWF) is synthesized in endothelial cells and platelet precursors. Type 3 patients with Pro2808Leufs*24 have lower bleeding scores than other type 3s. The Pro2808Leufs*24 variant was examined in patient platelets and endothelial cells. Type 3s with this variant contain releaseable VWF, possibly reducing bleeding. SUMMARY:Background A novel variant, p.Pro2808Leufs*24, in the von Willebrand factor (VWF) gene was previously identified in the Canadian von Willebrand disease (VWD) patient population. Clinical observations of type 3 VWD patients with this variant indicate a milder bleeding phenotype compared with other type 3 patients. Objective To assess the effect of the Pro2808Leufs*24 variant on the molecular pathogenesis of VWD and correlate this with the phenotype observed in patients. Patients/Methods Phenotypic data from individuals in the Canadian type 3 VWD study were analyzed. VWF expression in platelets and plasma was assessed via immunoblotting. Cellular expression of VWF in platelets and blood outgrowth endothelial cells (BOEC) was examined via immunofluorescence microscopy and biochemical analysis in a type 3 index case and family member with Pro2808Leufs*24. Results Twenty-six individuals with the Pro2808Leufs*24 variant (16 type 3 VWD homozygous or compound heterozygous and 10 heterozygous family members) were studied. Bleeding scores were lower in type 3 patients with Pro2808Leufs*24 compared with type 3 patients with other variants, confirming a milder bleeding phenotype. Immunoblotting of platelet lysates detected VWF in the platelets of type 3 patients with Pro2808Leufs*24. Examination of an index case detected VWF within platelets via immunofluorescence microscopy, and in vitro experiments showed that this VWF was released upon platelet activation. Patient BOECs showed decreased VWF synthesis and secretion, although some VWF-containing granules were observed. Conclusion Type 3 VWD patients with the Pro2808Leufs*24 have bioavailable platelet-derived VWF that may produce a milder bleeding phenotype than other type 3s.

Dataset Information

A mechanism for localized dynamics-driven affinity regulation of the binding of von Willebrand factor to platelet glycoprotein Ib?.

Publications

A mechanism for localized dynamics-driven affinity regulation of the binding of von Willebrand factor to platelet glycoprotein Ibα.

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