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Measurement of Factor V Activity in Human Plasma Using a Microplate Coagulation Assay
Published on: September 9, 2012
Completed three-dimensional model of human coagulation factor va. Molecular dynamics simulations and structural
Tivadar Orban1, Michael Kalafatis, Valentin Gogonea
1Department of Chemistry, Cleveland State University, Ohio 44195, USA.
Biochemistry
|September 28, 2005
Summary
This study presents a complete computational model of human factor Va, crucial for blood clotting. The model explains how activated protein C (APC) inactivates factor Va, revealing key mechanisms in prothrombinase complex function.
Area of Science:
- Biochemistry and Molecular Biology
- Structural Biology
- Hematology
Background:
- Factor Va is essential for prothrombinase complex assembly and efficient thrombin generation.
- Previous homology models of factor Va were incomplete and lacked dynamic information.
- New X-ray structures revealed different domain arrangements, necessitating model refinement.
Purpose of the Study:
- To create a complete, dynamic 3D model of human factor Va in solution.
- To incorporate missing carboxyl-terminal residues into the existing homology model.
- To elucidate the mechanism of factor Va inactivation by activated protein C (APC).
Main Methods:
- Sequence alignment of human and bovine factor Va C1 and C2 domains.
- Modification of a homology model using X-ray structure templates.
- Computational determination of the carboxyl-terminal peptide structure.
- Molecular dynamics simulations to analyze cofactor folding and dynamics.
Main Results:
- A complete 3D model of human factor Va was generated, including dynamic domain movements.
- The model demonstrates that APC cleavage at Arg(306) is necessary for A2 domain dissociation.
- Differences in APC inactivation rates for factor Va and factor V Leiden are explained by cleavage kinetics at Arg(306).
Conclusions:
- The developed complete model of human factor Va provides a foundation for understanding prothrombinase complex function.
- The model accurately accounts for experimental observations regarding factor Va inactivation by APC.
- This structural insight is crucial for comprehending blood coagulation mechanisms and related disorders.
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