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Theoretical and experimental study of the D2194G mutation in the C2 domain of coagulation factor V
- Biophys. J
, 2004
"... ABSTRACT Coagulation factor V (FV) is a large plasma glycoprotein with functions in both the pro- and anticoagulant pathways. In carriers of the so-called R2-FV haplotype, the FV D2194G mutation, in the C2 membrane-binding domain, is associated with low expression levels, suggesting a potential fold ..."
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ABSTRACT Coagulation factor V (FV) is a large plasma glycoprotein with functions in both the pro- and anticoagulant pathways. In carriers of the so-called R2-FV haplotype, the FV D2194G mutation, in the C2 membrane-binding domain, is associated with low expression levels, suggesting a potential folding/stability problem. To analyze the molecular mechanisms potentially responsible for this in vitro phenotype, we used molecular dynamics (MD) and continuum electrostatic calculations. Implicit solvent simulations were performed on the x-ray structure of the wild-type C2 domain and on a model of the D2194G mutant. Because D2194 is located next to a disulfide bond (S-S bond), MD calculations were also performed on S-S bond depleted structures. D2194 is part of a salt-bridge network and investigations of the stabilizing/destabilizing role of these ionic interactions were carried out. Five mutant FV molecules were created and the expression levels measured with the aim of assessing the tolerance to amino acid changes in this region of molecule. Analysis of the MD trajectories indicated increased flexibility in some areas and energetic comparisons suggested overall destabilization of the structure due to the D2194G mutation. This substitution causes electrostatic destabilization of the domain by;3 kcal/mol. Together these effects likely explain the lowered expression levels in R2-FV carriers.
Chalcones as Possible Anti-Inflammatory Agents
"... This is an Open Access article distributed under the terms of the Creative Commons Attribution License ..."
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This is an Open Access article distributed under the terms of the Creative Commons Attribution License
METHODOLOGY ARTICLE Open Access Predicting
"... protein ligand binding motions with the conformation explorer ..."
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"... Structural and functional plasticity of subcellular tethering, targeting and processing of RPGRIP1 by RPGR isoforms ..."
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Structural and functional plasticity of subcellular tethering, targeting and processing of RPGRIP1 by RPGR isoforms
