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The catch bond mechanism between von Willebrand factor and platelet surface receptors investigated by molecular dynamics simulations.

ABSTRACT: The multi-domain protein von Willebrand factor is crucial in the blood coagulation process at high shear. The A1 domain binds to the platelet surface receptor glycoprotein Ibalpha (GpIb alpha) and this interaction is known to be strengthened by tensile force. The molecular mechanism behind this observation was investigated here by molecular dynamics simulations. The results suggest that the proteins unbind through two distinct pathways depending whether a high-tensile force is applied or whether unbinding happens through thermal fluctuations. In the high-force unbinding pathway the A1 domain was observed to rotate away from the C-terminus of GpIb alpha. In contrast, during thermal unbinding the A1 domain rotated in the opposite direction as in the high-force pathway and the distance between the terminii of A1 and the GpIb alpha C-terminus shortened. This shortening was reduced and the lifetime of the bond extended if a moderate tensile force was applied across the complex. This suggests that the thermal unbinding pathway is inhibited by a moderate tensile force which is in agreement with the catch bond property shown previously in single molecule experiments. A designed mutant of GpIb alpha is suggested here in order to test in vitro the thermal unbinding pathway observed in silico.

SUBMITTER: Interlandi G

PROVIDER: S-EPMC6107302 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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The catch bond mechanism between von Willebrand factor and platelet surface receptors investigated by molecular dynamics simulations.

Interlandi Gianluca G Thomas Wendy W

Proteins 20100801 11

The multi-domain protein von Willebrand factor is crucial in the blood coagulation process at high shear. The A1 domain binds to the platelet surface receptor glycoprotein Ibalpha (GpIb alpha) and this interaction is known to be strengthened by tensile force. The molecular mechanism behind this observation was investigated here by molecular dynamics simulations. The results suggest that the proteins unbind through two distinct pathways depending whether a high-tensile force is applied or whether ...[more]

PMID: 20602356

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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.

Project description:Thrombocytopenia and platelet dysfunction are commonly observed in patients with dengue virus (DENV) infection and may contribute to complications such as bleeding and plasma leakage. The etiology of dengue-associated thrombocytopenia is multifactorial and includes increased platelet clearance. The binding of the coagulation protein von Willebrand factor (VWF) to the platelet membrane and removal of sialic acid (desialylation) are two well-known mechanisms of platelet clearance, but whether these conditions also contribute to thrombocytopenia in dengue infection is unknown. In two observational cohort studies in Bandung and Jepara, Indonesia, we show that adult patients with dengue not only had higher plasma concentrations of plasma VWF antigen and active VWF, but that circulating platelets had also bound more VWF to their membrane. The amount of platelet-VWF binding correlated well with platelet count. Furthermore, sialic acid levels in dengue patients were significantly reduced as assessed by the binding of Sambucus nigra lectin (SNA) and Maackia amurensis lectin II (MAL-II) to platelets. Sialic acid on the platelet membrane is neuraminidase-labile, but dengue virus has no known neuraminidase activity. Indeed, no detectable activity of neuraminidase was present in plasma of dengue patients and no desialylation was found of plasma transferrin. Platelet sialylation was also not altered by in vitro exposure of platelets to DENV nonstructural protein 1 or cultured DENV. In contrast, induction of binding of VWF to glycoprotein 1b on platelets using the VWF-activating protein ristocetin resulted in the removal of platelet sialic acid by translocation of platelet neuraminidase to the platelet surface. The neuraminidase inhibitor oseltamivir reduced VWF-induced platelet desialylation. Our data demonstrate that excessive binding of VWF to platelets in dengue results in neuraminidase-mediated platelet desialylation and platelet clearance. Oseltamivir might be a novel treatment option for severe thrombocytopenia in dengue infection.

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The catch bond mechanism between von Willebrand factor and platelet surface receptors investigated by molecular dynamics simulations.

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The catch bond mechanism between von Willebrand factor and platelet surface receptors investigated by molecular dynamics simulations.

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