Molecular models of the procoagulant factor VIIIa-factor IXa complex.
BACKGROUND
Formation of the intrinsic tenase complex is an essential event in the procoagulant reactions that lead to clot formation. The tenase complex is formed when the activated serine protease, Factor IXa (FIXa), and its cofactor Factor VIIIa (FVIIIa) assemble on a phospholipid surface to proteolytically convert the zymogen Factor X (FX) into its active form FXa. The physiological relevance of the tenase complex is evident in hemophilia A or B patients who present with bleeding disorders.


OBJECTIVE
The purpose of this study was to establish three-dimensional (3D) models of the FVIIIa-FIXa complex.


METHODS
First, we built two new theoretical models of FVIIIa via homology modeling, inter-domain docking and loop simulation algorithms as well as a model for FIXa. This was followed by pseudo-Brownian protein-protein docking in internal coordinates with the ICM (Internal Coordinates Mechanics) program between the two FVIIIa and the FIXa structures.


RESULTS
Ten representative models of this complex are presented based on agreements with known experimental data and according to structural criteria.


CONCLUSIONS
These novel 3D models will help guide future site directed mutagenesis aimed at improving the functionality of FVIIIa and/or FIXa and will contribute to a better understanding of the role of this macromolecular complex in the blood coagulation cascade.
Autin
L
L
Inserm U648, Paris 5 University, 4 Ave de l'Observatoire, Paris, France.
Miteva
M A
MA
Lee
W H
WH
Mertens
K
K
Radtke
K-P
KP
Villoutreix
B O
BO
D000465:Algorithms; D001777:Blood Coagulation; D003546:Cysteine Endopeptidases / Q000737:chemistry; D015949:Factor IXa / Q000737:chemistry*; D015944:Factor VIIIa / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry; D009363:Neoplasm Proteins / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D040681:Structural Homology, Protein
D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D015944:Factor VIIIa; D015949:Factor IXa; D003546:Cysteine Endopeptidases; C030910:cancer procoagulant