COAGULATION FACTOR IX-BINDING PROTEIN A
Trimeresurus flavoviridis(habu snake)
The cascade of blood coagulation is caused by a collection of proteins known as the blood coagulation factors. The cascade terminates with the formation of cross-linked fibrin polymer closing damaged blood vessels like a plug. The fibrin polymer is formed through aggregation of fibrin monomers created from a protein fibrinogen through the cleaving action of another protein, thrombin. The whole cascade involves two pathways, the intrinsic and the extrinsic pathway. The two pathways join forming activated factor X protein (Xa) and using Xa to activate thrombin. Essentially all the proteins involved in the cascade contain a protease part whose function is to activate the next protein in the cascade by cutting its chain, generating the active protein from an inactive precursor protein. They participate in two mechanisms: preventing the loss of blood (hemorrhage) and the undesired formation of fibrin clots (thrombosis). Prevention of thrombosis by inhibition of blood clotting is of interest to the pharmaceutical industry. An important structural part of the clotting factors is an exposed segment know as the membrane binding domain. This domain attaches the factors to the surface of endothelial cells which make up part of the surface blood vessels. PDB entry PDB:1IOD shows the structure of a complex of such a domain with an inhibitory protein from snake venom, specific for factor X.
The structure shown here gives another example of such an inhibitory protein, again from snake venom, this one specific for factor IX. Factor IX is part of the intrinsic pathway and involved in the activation of factor X. The protein consists of two subunits forming a dimer. While most of the individual subunits are spatially separated, an extended loop from one subunit protrudes into the area of the other subunit and vice versa. In addition they are held together by a disulfide connecting a cysteine from one subunit to a cysteine from the other. While only the inhibitory protein is shown here, without the protein it will bind to, the concave groove formed at the intersection of the two subunits clearly shows where the membrane binding domain from factor IX would be located.
Protein Data Bank (PDB)
Mizuno, H. Fujimoto, Z. Koizumi, M. Kano, H. Atoda, H. Morita, T.; "Crystal structure of coagulation factor IX-binding protein from habu snake venom at 2.6 A: implication of central loop swapping based on deletion in the linker region."; J. Mol. Biol.; (1999) 289:103-112 PubMed:10339409.
Author: Arno Paehler