Arginine-79 in the first epidermal growth factor domain of factor VII is essential for the interaction with tissue factor

Sridhara, Sampath; Clarke, BJ; Blajchman, MA

doi:10.1097/00001721-199306000-00019

Cited by 10 publications

(13 citation statements)

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“…Studies on the crystal structure of TF and FVII, as well as mutational studies, have identified several areas important for binding. 9,17,18 We chose three linear binding sequences from FVII. The first sequence is from the EGF-2 domain and contains arginine 79, which has been shown to be important for TF binding by crystal structure interactions 19 and through mutational studies.…”

Section: Resultsmentioning

confidence: 99%

“…The first sequence is from the EGF-2 domain and contains arginine 79, which has been shown to be important for TF binding by crystal structure interactions 19 and through mutational studies. 17,18 This sequence, consisting of the amino acids EGRNCETHKDDQL, is referred to as the EGR sequence ( Figure 1A). The next sequence is located on the heavy chain of FVII, forms an α-helix, and contains the amino acids methionine 306 and aspartate 309, both of which have been shown to be important in the binding of FVII to TF.…”

Section: Resultsmentioning

confidence: 99%

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Tissue-Factor Targeted Peptide Amphiphile Nanofibers as an Injectable Therapy To Control Hemorrhage

et al. 2015

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Noncompressible torso hemorrhage is a leading cause of mortality in civilian and battlefield trauma. We sought to develop an i.v.-injectable, tissue factor (TF)-targeted nanotherapy to stop hemorrhage. Tissue factor was chosen as a target because it is only exposed to the intravascular space upon vessel disruption. Peptide amphiphile (PA) monomers that self-assemble into nanofibers were chosen as the delivery vehicle. Three TF-binding sequences were identified (EGR, RLM, and RTL), covalently incorporated into the PA backbone, and shown to self-assemble into nanofibers by cryo-transmission electron microscopy. Both the RLM and RTL peptides bound recombinant TF in vitro. All three TF-targeted nanofibers bound to the site of punch biopsy-induced liver hemorrhage in vivo, but only RTL nanofibers reduced blood loss versus sham (53% reduction, p < 0.05). Increasing the targeting ligand density of RTL nanofibers yielded qualitatively better binding to the site of injury and greater reductions in blood loss in vivo (p < 0.05). In fact, 100% RTL nanofiber reduced overall blood loss by 60% versus sham (p < 0.05). Evaluation of the biocompatibility of the RTL nanofiber revealed that it did not induce RBC hemolysis, did not induce neutrophil or macrophage inflammation at the site of liver injury, and 70% remained intact in plasma after 30 min. In summary, these studies demonstrate successful binding of peptides to TF in vitro and successful homing of a TF-targeted PA nanofiber to the site of hemorrhage with an associated decrease in blood loss in vivo. Thus, this therapeutic may potentially treat noncompressible hemorrhage.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Tissue-Factor Targeted Peptide Amphiphile Nanofibers as an Injectable Therapy To Control Hemorrhage

et al. 2015

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“…The following surface-exposed residues in VIIa are known to play a functionally important role: Arg-79 in EGF1 (4,5) and Arg-304 [c162] (6,7) in the protease domain are implicated in binding to TF; whereas Arg-290 [c148] (8) and Lys-341 [c192] (9) are critical for proteolytic function and substrate specificity of VIIa. In the present study, we used the structurally conservative approach of alanine scanning mutagenesis of surface residues (10) to establish an extensive list of residues that are functionally involved in cofactor interaction and substrate factor X (X) activation.…”

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confidence: 99%

Identification of surface residues mediating tissue factor binding and catalytic function of the serine protease factor VIIa

Dickinson

Kelly

Ruf

1996

Proc. Natl. Acad. Sci. U.S.A.

188

242

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Factor VIIa (VIIa), the serine protease that initiates the coagulation pathways, is catalytically activated upon binding to its cell surface receptor and cofactor tissue factor (TF). This study provides a comprehensive analysis of the functional surface of VIIa by alanine scanning mutagenesis of 112 residues. Residue side chains were defined which contribute to TF binding and factor X hydrolysis. Energetically important binding contacts at the interface with TF were identified in the first epidermal growth factor domain of VIIa (Gln-64, Ile-69, Phe-71, Arg-79) and in the protease domain (Arg-277, Met-306, Asp-309). The observed energetic defects are in good agreement with the corresponding residues in TF, suggesting that the VIIa light chain plays a prominent role in high affinity binding of cofactor. Mutation of protease domain interface residues indicated that TF allosterically inf luences the active site of VIIa. Stabilization of a labile zymogen to enzyme transition could explain the activating effect of TF on VIIa catalytic function. Residues important for factor X hydrolysis were found in three regions of the protease domain: (i) specificity determinants in the catalytic cleft and adjacent loops, (ii) an exosite near the TF binding site, and (iii) a large electronegative exosite which is in a position analogous to the basic exosite I of thrombin. TF regions involved in factor X activation are positioned on the same face of the TF⅐VIIa complex as the two exosites identified on the protease domain surface, providing evidence for an extended interaction of TF⅐VIIa with macromolecular substrate.Coagulation factor VIIa (VIIa) is the initiating protease of the coagulation pathways (1). VIIa binds to its cellular receptor and catalytic cofactor, the transmembrane glycoprotein tissue factor (TF). Interaction of VIIa with TF markedly enhances the catalytic activity of the serine protease which is a poor enzyme when free in solution. However, the mechanism by which the cofactor achieves this activation is unknown. VIIa is a multidomain enzyme characterized by an amino-terminal ␥-carboxyglutamic acid-rich (Gla) domain, two epidermal growth factor (EGF)-like modules and a trypsin-like serine protease domain. Various experimental approaches indicate that the Gla-domain, the first EGF domain (EGF1), and the protease domain provide the most significant contributions to the interaction with TF (reviewed in ref.2). The recently determined three-dimensional structure of the TF⅐VIIa complex revealed a discontinuous interaction involving each domain of VIIa and the two fibronectin type III modules that constitute the cytokine receptor-like extracellular domain of TF (3).While extensive mutagenesis of TF has defined the functional and energetic importance of residues that interface with VIIa, there is little information on the contributions of specific amino acid side chains in VIIa to TF binding or proteolytic function. The following surface-exposed residues in VIIa are known to play a functionally important role: Arg...

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“…The Arg79 seems to tether the protein to its receptor, whereas residue Arg304 is needed for the full catalytic function of the found protease. [69][70][71] As the complex FVII-tissue factor is widely known to play a pivotal role in triggering blood clotting, it is clear that inhibitors of the complex could represent an important potential therapeutic advance. In nature, TFPI plays a balancing role, modulating and controlling the activity of the complex.…”

Section: Factor Vii-tissue Factor Inhibitorsmentioning

confidence: 99%

The Story of Serum Prothrombin Conversion Accelerator, Proconvertin, Stable Factor, Cothromboplastin, Prothrombin Accelerator or Autoprothrombin I, and Their Subsequent Merging into Factor VII

Girolami

Cosi

Sommer

et al. 2015

Semin Thromb Hemost

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Factor VII (FVII) deficiency is one of the two congenital coagulation disorders that was not discovered by the description of a new bleeding patient whose clotting pattern did not fit the blood coagulation knowledge of the time (the other is factor XIII deficiency). The existence of an additional factor capable of accelerating the conversion of prothrombin into thrombin was suspected before 1951, the year in which the first family with FVII deficiency was discovered. As several investigators were involved in the discovery of FVII deficiency from both sides of the Atlantic, several different names were tentatively suggested to define this entity, namely stable factor (in contrast with labile factor or FV), cothromboplastin, proconvertin, serum prothrombin conversion accelerator, prothrombin acceleration, and autoprothrombin I. The last term was proposed by those who denied the existence of this new entity, which was instead considered to be a derivate of prothrombin activation, namely autoprothrombin. The description of several families, from all over the world, of the same defect, however clearly demonstrated the singularity of the condition. Factor VII was then proposed to define this protein. In subsequent years, several variants were described with peculiar reactivity toward tissue thromboplastins of different origin. Molecular biology techniques demonstrated several gene mutations, usually missense mutations, often involving exon 8 of the FVII gene. Later studies dealt with the relation of FVII with tissue factor and activated FVII (FVIIa). The evaluation of circulating FVIIa was made possible by the use of a truncated form of tissue factor, which is only sensitive to FVIIa present in the circulation. The development of FVII concentrates, both plasma derived and recombinant, has facilitated therapeutic management of FVII-deficient patients. The use of FVIIa concentrates was noted to be associated with the occasional occurrence of thrombotic events, mainly venous. Total or partial liver transplants have been performed with success in these patients and have "cured" their deficiencies. Prenatal diagnosis has also been performed and recent research involves the development of inhibitors of FVII + tissue factor complex or of FVIIa. This approach, if successful, could provide another antithrombotic therapeutics tool. The story of FVII well summarizes the efforts of both theoretical and clinical approaches in the characterization of a coagulation disorder, that is, among the rare bleeding conditions, most frequently encountered in clinical practice.

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Arginine-79 in the first epidermal growth factor domain of factor VII is essential for the interaction with tissue factor

Cited by 10 publications

References 0 publications

Tissue-Factor Targeted Peptide Amphiphile Nanofibers as an Injectable Therapy To Control Hemorrhage

Tissue-Factor Targeted Peptide Amphiphile Nanofibers as an Injectable Therapy To Control Hemorrhage

Identification of surface residues mediating tissue factor binding and catalytic function of the serine protease factor VIIa

The Story of Serum Prothrombin Conversion Accelerator, Proconvertin, Stable Factor, Cothromboplastin, Prothrombin Accelerator or Autoprothrombin I, and Their Subsequent Merging into Factor VII

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