Dynamical view of membrane binding and complex formation of human factor VIIa and tissue factor

被引:58
作者
Ohkubo, Y. Z. [1 ,2 ]
Morrissey, J. H. [2 ,3 ]
Tajkhorshid, E. [1 ,2 ,3 ,4 ]
机构
[1] Univ Illinois, Beckman Inst Adv Sci & Technol, Urbana, IL 61801 USA
[2] Univ Illinois, Dept Biochem, Urbana, IL 61801 USA
[3] Univ Illinois, Coll Med, Urbana, IL 61801 USA
[4] Univ Illinois, Ctr Biophys & Computat Biol, Urbana, IL 61801 USA
关键词
coagulation cascade; factor VIIa; GLA domain; molecular dynamics simulation; protein-protein interaction; tissue factor; CARBOXYGLUTAMIC ACID DOMAIN; BLOOD-COAGULATION FACTOR; CRYSTAL-STRUCTURE; GLA DOMAIN; FACTOR-X; MOLECULAR-DYNAMICS; FACTOR-IX; ANTICOAGULANT PROTEIN; ENERGY-TRANSFER; FACTOR REGION;
D O I
10.1111/j.1538-7836.2010.03826.x
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background: The molecular mechanism of enhancement of the enzymatic activity of factor VIIa by tissue factor (TF) is not fully understood, primarily because of the lack of atomic models for the membrane-bound form of the TF-FVIIa complex. Objectives: To construct the first membrane-bound model of the TF-FVIIa complex, and to investigate the dynamics of the complex in solution and on the surface of anionic membranes by using large-scale molecular dynamics (MD) simulations in full atomic detail. Methods: Membrane-bound models of the TF-FVIIa complex and the individual factors were constructed and subjected to MD simulations, in order to characterize protein-protein and protein-lipid interactions, and to investigate the dynamics of TF and FVIIa. Results: The MD trajectories reveal that isolated FVIIa undergoes large structural fluctuation, primarily due to the hinge motions between its domains, whereas soluble TF (sTF) is structurally stable. Upon complex formation, sTF restricts the motion of FVIIa significantly. The results also show that, in the membrane-bound form, sTF directly interacts with the lipid headgroups, even in the absence of FVIIa. Conclusion: The first atomic models of membrane-bound sTF-FVIIa, FVIIa and sTF are presented, revealing that sTF forms direct contacts with the lipids, both in the isolated form and in complex with FVIIa. The main effect of sTF binding to FVIIa is spatial stabilization of the catalytic site of FVIIa, which ensures optimal interaction with the substrate, FX.
引用
收藏
页码:1044 / 1053
页数:10
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