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Molecular dynamics analysis of a novel ?3 Pro189Ser mutation in a patient with glanzmann thrombasthenia differentially affecting ?IIb?3 and ?v?3 expression.

ABSTRACT: Mutations in ITGA2B and ITGB3 cause Glanzmann thrombasthenia, an inherited bleeding disorder in which platelets fail to aggregate when stimulated. Whereas an absence of expression or qualitative defects of ?IIb?3 mainly affect platelets and megakaryocytes, ?v?3 has a widespread tissue distribution. Little is known of how amino acid substitutions of ?3 comparatively affect the expression and structure of both integrins. We now report computer modelling including molecular dynamics simulations of extracellular head domains of ?IIb?3 and ?v?3 to determine the role of a novel ?3 Pro189Ser (P163S in the mature protein) substitution that abrogates ?IIb?3 expression in platelets while allowing synthesis of ?v?3. Transfection of wild-type and mutated integrins in CHO cells confirmed that only ?v?3 surface expression was maintained. Modeling initially confirmed that replacement of ?IIb by ?v in the dimer results in a significant decrease in surface contacts at the subunit interface. For ?IIb?3, the presence of ?3S163 specifically displaces an ?-helix starting at position 259 and interacting with ?3R261 while there is a moderate 11% increase in intra-subunit H-bonds and a very weak decrease in the global H-bond network. In contrast, for ?v?3, S163 has different effects with ?3R261 coming deeper into the propeller with a 43% increase in intra-subunit H-bonds but with little effect on the global H-bond network. Compared to the WT integrins, the P163S mutation induces a small increase in the inter-subunit fluctuations for ?IIb?3 but a more rigid structure for ?v?3. Overall, this mutation stabilizes ?v?3 despite preventing ?IIb?3 expression.

SUBMITTER: Laguerre M

PROVIDER: S-EPMC3827234 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Molecular dynamics analysis of a novel β3 Pro189Ser mutation in a patient with glanzmann thrombasthenia differentially affecting αIIbβ3 and αvβ3 expression.

Laguerre Michel M Sabi Essa E Daly Martina M Stockley Jacqueline J Nurden Paquita P Pillois Xavier X Nurden Alan T AT

PloS one 20131113 11

Mutations in ITGA2B and ITGB3 cause Glanzmann thrombasthenia, an inherited bleeding disorder in which platelets fail to aggregate when stimulated. Whereas an absence of expression or qualitative defects of αIIbβ3 mainly affect platelets and megakaryocytes, αvβ3 has a widespread tissue distribution. Little is known of how amino acid substitutions of β3 comparatively affect the expression and structure of both integrins. We now report computer modelling including molecular dynamics simulations of ...[more]

PMID: 24236036

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Project description:Standard treatment for Glanzmann thrombasthenia is platelet transfusion. Recombinant activated factor VII has been shown to be successful in patients with Glanzmann thrombasthenia with platelet antibodies or who are refractory to platelet transfusions. The Glanzmann Thrombasthenia Registry prospectively collected worldwide information on the effectiveness and safety of platelet transfusion, recombinant activated factor VII and/or antifibrinolytics for the treatment of bleeds in patients with Glanzmann thrombasthenia. Data relating to 829 non-surgical bleeding episodes were entered into the Glanzmann Thrombasthenia Registry (severe/moderate: 216/613; spontaneous/post-traumatic: 630/199). Recombinant activated factor VII alone was used in 124/829 bleeds, recombinant activated factor VII+antifibrinolytics in 107/829, platelets±antifibrinolytics in 312/829, antifibrinolytics alone in 219/829, and recombinant activated factor VII+platelets±antifibrinolytics in 67/829. The proportion of successful treatments to stop bleeding was 91.0% in cases treated with recombinant activated factor VII only, 82.7% for recombinant activated factor VII+antifibrinolytics, 72.7% for treatment with recombinant activated factor VII+platelets±antifibrinolytics, 78.8% for platelets±antifibrinolytics and 84.7% for antifibrinolytics alone. Treatment failure was documented in 18 bleeding events (2% of the total treatments), the majority of which were in patients receiving treatment with antifibrinolytics; bleeding re-started in 6% of bleeds after initial effective treatment. Thirty-five adverse events were reported, none of which was a thromboembolic event. Among treatments that included recombinant activated factor VII, only one patient reported three possibly drug-related non-serious adverse events (nausea, dyspnea and headache). To conclude, non-surgical bleeds were common and often severe in Glanzmann thrombasthenia; both platelets and recombinant activated factor VII appeared to be effective, and with good safety profiles, for the treatment of non-surgical bleeds. This trial was registered at clinicaltrials.gov identifier: NCT01476423.

Dataset Information

Molecular dynamics analysis of a novel ?3 Pro189Ser mutation in a patient with glanzmann thrombasthenia differentially affecting ?IIb?3 and ?v?3 expression.

Publications

Molecular dynamics analysis of a novel β3 Pro189Ser mutation in a patient with glanzmann thrombasthenia differentially affecting αIIbβ3 and αvβ3 expression.

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