Regulation of Extrinsic Pathway Factor Xa Formation by Tissue Factor Pathway Inhibitor

Baugh, Robert J.; Broze, George J.; Krishnaswamy, Sriram

doi:10.1074/jbc.273.8.4378

Cited by 204 publications

(233 citation statements)

References 49 publications

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“…Computational analysis of the full-length deduced amino acid sequences suggested that Seq7 was homologous to TFPI, a Kunitz-type protein, possessing 3 KPI domains, which is involved in the regulation of blood coagulation by inhibiting FXa and FVIIa. 34 Seq7 contains a domain with homology to the KPI domain 1. Therefore, Seq7 might inhibit factors in the vertebrate coagulation cascade such as FVIIa.…”

Section: Discussionmentioning

confidence: 99%

Isolation of Ixodes ricinus salivary gland mRNA encoding factors induced during blood feeding.

Leboulle¹,

Rochez²,

Louahed³

et al. 2002

The American Journal of Tropical Medicine and Hygiene

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Abstract. In tick salivary glands, genes induced during blood feeding result in the expression of new proteins secreted into tick saliva. These proteins are potentially involved in modulation of vertebrate host immune and hemostatic responses. In this study, subtractive and full-length cDNA libraries were constructed by use of mRNA extracted from salivary glands of unfed and 5-day engorged Ixodes ricinus. Sequences from these 2 libraries were compared with European Molecular Biology Laboratory (EMBL)/GenBank databases, which led to their classification into 2 major groups. The first group comprises cDNAs that failed to match or showed low homology to genes of known function. The second group includes sequences that showed high homology to genes of known function-for example, anticoagulants, inhibitors of platelet aggregation, and immunomodulatory proteins. Analyses of corresponding proteins suggest that they may be secreted by salivary gland cells. To study the properties of the recombinant proteins, selected cDNAs were expressed in mammalian or bacterial systems.

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Section: Discussionmentioning

confidence: 99%

Isolation of Ixodes ricinus salivary gland mRNA encoding factors induced during blood feeding.

Leboulle¹,

Rochez²,

Louahed³

et al. 2002

The American Journal of Tropical Medicine and Hygiene

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“…The zymogen preparation was depleted of traces of active Xa as described (26). Factor X was proteolytically activated to factor Xa using the purified X activator isolated from Russell's viper venom and further purified by affinity chromatography on benzamidine-Sepharose (27).…”

Section: Methodsmentioning

confidence: 99%

“…All kinetic studies were performed in 20 mM Hepes, 0.15 M NaCl, 5 mM CaCl 2 , 0.1% (w/v) PEG-8000, pH 7.50 (designated as Assay Buffer). Continuous and discontinuous kinetic studies were performed using 96-well plates (Corning 9710, Corning, NY) pretreated with Tween 20 and air-dried prior to use as described previously (26) to minimize adsorption artifacts.…”

Section: Methodsmentioning

confidence: 99%

Exosite Interactions Determine the Affinity of Factor X for the Extrinsic Xase Complex

Baugh

Dickinson²,

Ruf³

et al. 2000

Journal of Biological Chemistry

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106

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The initiation of coagulation results from the activation of factor X by an enzyme complex (Xase) composed of the trypsin-like serine proteinase, factor VIIa, bound to tissue factor (TF) on phospholipid membranes. We have investigated the basis for the protein substrate specificity of Xase using TF reconstituted into vesicles of phosphatidylcholine, phosphatidylserine, or pure phosphatidylcholine. We show that occupation of the active site of VIIa within Xase by a reversible inhibitor or an alternate peptidyl substrate is sufficient to exclude substrate interactions at the active site but does not alter the affinity of Xase for factor X. This is evident as classical competitive inhibition of peptidyl substrate cleavage but as classical noncompetitive inhibition of factor X activation by active site-directed ligands. This implies that the productive recognition of factor X by Xase arises from a multistep reaction requiring an initial interaction at sites on the enzyme complex distinct from the active site (exosites), followed by active site interactions and bond cleavage. Exosite interactions determine protein substrate affinity, whereas the second binding step influences the maximum catalytic rate for the reaction. We also show that competitive inhibition can be achieved by interfering with exosite binding using factor X derivatives that are expected to have limited or abrogated interactions with the active site of VIIa within Xase. Thus, substrate interactions at exosites, sites removed from the active site of VIIa within the enzyme complex, determine affinity and binding specificity in the productive recognition of factor X by the VIIa-TF complex. This may represent a prevalent strategy through which distinctive protein substrate specificities are achieved by the homologous enzymes of coagulation.The proteolytic activation of factor X by the extrinsic pathway is considered the initiating step of the blood coagulation cascade following vascular damage (4 -7). The conversion of the zymogen, factor X, to the serine protease, factor Xa, is accomplished by the extrinsic Xase complex that assembles through reversible interactions between the serine proteinase, factor VIIa, and the integral membrane cofactor protein, tissue factor (TF) 1 (4, 5). Although this complex can catalyze the proteolytic activation of either factors X or IX to their respective active enzymes with comparable catalytic efficiency, Xa formation is considered essential for the initiation of the coagulation cascade, whereas IXa formation may be important for sustained flux toward thrombin formation (4 -7).The catalytic domains of the serine proteinases of coagulation are highly homologous to each other as well as to trypsin, the archetypical arginine-specific serine proteinase (8, 9). Despite these similarities, the coagulation proteinases act on their protein substrates with narrow and distinctive specificity (10). The molecular basis for the defined protein substrate specificity of the coagulation enzyme complexes is not well understood. It is i...

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“…The second Kunitz domain binds first to a molecule of FXa and deactivates it. The first domain then rapidly binds to an adjacent TF-FVIIa complex, preventing further activation of Factor X [40][41][42]. The formation of this quaternary compound is necessary for the inhibitory action of TFPI on the TF-FVIIa complex.…”

Section: ó 2004 Blackwell Publishing Ltdmentioning

confidence: 99%

Tissue factor and tissue factor pathway inhibitor

Price

Thompson²,

Kam

2004

Anaesthesia

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SummaryThe classical 'cascade ⁄ waterfall' hypothesis formulated to explain in vitro coagulation organised the amplification processes into the intrinsic and extrinsic pathways. Recent molecular biology and clinical data indicate that tissue factor ⁄ factor-VII interaction is the primary cellular initiator of coagulation in vivo. The process of blood coagulation is divided into an initiation phase followed by a propagation phase. The discovery of tissue factor pathway inhibitor further supports the revised theory of coagulation. Tissue factor is also a signalling receptor. Recent evidence has shown that blood-borne tissue factor has an important procoagulant function in sepsis, atherosclerosis and cancer, and other functions beyond haemostasis such as immune function and metastases.

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Regulation of Extrinsic Pathway Factor Xa Formation by Tissue Factor Pathway Inhibitor

Cited by 204 publications

References 49 publications

Isolation of Ixodes ricinus salivary gland mRNA encoding factors induced during blood feeding.

Isolation of Ixodes ricinus salivary gland mRNA encoding factors induced during blood feeding.

Exosite Interactions Determine the Affinity of Factor X for the Extrinsic Xase Complex

Tissue factor and tissue factor pathway inhibitor

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