Factor VIIa-Tissue Factor: Functional Importance of Protein-Membrane Interactions

Abstract

Overall structure and function of TF-FVlla (1,18,19); it confers the ability to bind reversibly to anionic phospholipids. Next to the Gla-domain, and sometimes classified as part of it, is a short shetch of largely hydrophobic residues called the hydrophobic or aromatic stack. Next are two modules related to epidermal growth factor (EGF domains). EGFr, the more N-terminal of the two, contains a

Identification of a Basic Region on Tissue Factor that Interacts with the First Epidermal Growth Factor-like Domain of Factor X

“…In support of this proposal, recent fluorescence resonance energy transfer studies demonstrated that the activesite of fVIIa in complex with TF in the extrinsic Xase complex is also located far above the membrane surface (13). Thus, for effective recognition by fVIIa, both fIX and fX must also ‡To whom correspondence should be addressed: Alireza R. Rezaie, Ph.D., Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, 1402 S. Grand Blvd., St. Louis, MO 63104, Phone: (314) Fax: (314) assemble into the activation complex in the same extended conformations in order to maintain the activation peptides of the substrates at a similar distance to that of the active-site of fVIIa above the membrane surface (2,12,14,15).Like other vitamin K-dependent plasma serine proteases, the structure of fVIIa consists of a light and a heavy chain held together by a disulfide bond (16,17). The N-terminal light chain of fVIIa contains the Gla and two epidermal growth factor (EGF)-like domains and the Cterminal heavy chain contains the trypsin-like catalytic domain of the protease (16,17).…”

“…assemble into the activation complex in the same extended conformations in order to maintain the activation peptides of the substrates at a similar distance to that of the active-site of fVIIa above the membrane surface (2,12,14,15).…”

Staphylokinase-Annexin XI Chimera Exhibited Efficientin VitroThrombolytic Activities

“…[11][12][13][14] The activated platelets provide anionic surfaces for the assembly and catalysis of intrinsic tenase (VIIIa/IXa), prothrombinase (Va/Xa), and XIa complexes, leading to explosive generation of thrombin and consolidation of the fibrin-platelet plug. [15][16][17] Thus, rapid exposure of PS on the cell surfaces of platelets is the key thrombogenic stimulus initiating and propagating the clotting cascade. 9,10,17) Annexins (ANXs) are a family of calcium-dependent phospholipid binding proteins.…”

The Cofactor Function of the N-terminal Domain of Tissue Factor

“…Tissue factor (TF) 1 is an integral membrane cofactor that upon exposure to circulating blood binds with high affinity to factor VIIa (fVIIa) to catalyze the rapid activation of procoagulant zymogens factors IX and X, thereby initiating the blood clotting cascade (1)(2)(3). The structure of TF is composed of two fibrinonectin type III-like extracellular domains, a single membrane-spanning domain and a short cytoplasmic tail (4,5).…”

“…The structural data have indicated that the extracellular domains of TF make extensive interactions with both the light and heavy chains of fVIIa (10). It is believed that these interactions allosterically change the conformation of the active-site pocket of fVIIa, leading to a dramatic improvement in the catalytic efficiency of the protease toward both synthetic and natural macromolecular substrates (1). Most of the functionally critical residues of TF have been mapped by the Ala-scanning mutagenesis approaches (7,9,11).…”