1996
DOI: 10.1074/jbc.271.36.21752
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Substrate Recognition by Tissue Factor-Factor VIIa

Abstract: Tissue factor (TF) is the protein cofactor for factor VIIa (FVIIa), the first serine protease of the clotting cascade. Previous studies using alanine mutagenesis have identified TF residues Lys165 and Lys166 as important for factor X (FX) activation, hypothesizing either that these residues interact with phospholipid head groups or that they directly or indirectly promote macromolecular substrate binding. In the recently reported x-ray crystal structure of the isolated extracellular domain of TF, both Lys165 a… Show more

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Cited by 75 publications
(68 citation statements)
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“…Thus, for effective activation by factor VIIa, FX must also assemble into the complex in the same extended conformation to maintain the activation peptide of the substrate at the same distance above the membrane surface. Indeed, previous mutagenesis data have indicated that the Gla domain of FX has a recognition site for interaction with basic residues Lys 165 and Lys 166 in the membrane-proximal C-terminal domain of TF (25,26). The substitution of these residues of TF with Ala has resulted in mutants that have exhibited dramatically diminished cofactor activity in promoting the factor VIIa activation of the full-length but not Gla-domainless FX, suggesting that an interaction between the acidic Gla domain of FX and the two basic residues of TF makes a significant contribution to the stabilization of FX in the extrinsic Xase complex (26).…”
Section: Figmentioning
confidence: 99%
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“…Thus, for effective activation by factor VIIa, FX must also assemble into the complex in the same extended conformation to maintain the activation peptide of the substrate at the same distance above the membrane surface. Indeed, previous mutagenesis data have indicated that the Gla domain of FX has a recognition site for interaction with basic residues Lys 165 and Lys 166 in the membrane-proximal C-terminal domain of TF (25,26). The substitution of these residues of TF with Ala has resulted in mutants that have exhibited dramatically diminished cofactor activity in promoting the factor VIIa activation of the full-length but not Gla-domainless FX, suggesting that an interaction between the acidic Gla domain of FX and the two basic residues of TF makes a significant contribution to the stabilization of FX in the extrinsic Xase complex (26).…”
Section: Figmentioning
confidence: 99%
“…Indeed, previous mutagenesis data have indicated that the Gla domain of FX has a recognition site for interaction with basic residues Lys 165 and Lys 166 in the membrane-proximal C-terminal domain of TF (25,26). The substitution of these residues of TF with Ala has resulted in mutants that have exhibited dramatically diminished cofactor activity in promoting the factor VIIa activation of the full-length but not Gla-domainless FX, suggesting that an interaction between the acidic Gla domain of FX and the two basic residues of TF makes a significant contribution to the stabilization of FX in the extrinsic Xase complex (26). Thus, in this model of zymogen activation, it is expected that the interaction of the Gla domain of the FX mutant with the basic residues of the C-terminal TF would stabilize the substrate in an unproductive activation complex in which the activation peptide of the FX mutant is spatially aligned far below and out of reach of the active-site pocket of the protease.…”
Section: Figmentioning
confidence: 99%
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“…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). The characterization of these mutants has indicated that, in addition to interaction with fVIIa, the C-terminal membrane proximal domain of TF also provides binding sites for the ␥-carboxyglutamic acid and/or the first epidermal growth factor-like domains of factors IX and X thereby facilitating the assembly and optimal recognition of these substrates by fVIIa in the activation complex (11,12).…”
mentioning
confidence: 99%