Epidermal Growth Factor‐like Domains in the Vitamin K‐Dependent Clotting Factors

Stenflo, Johan; Öhlin, Ann-Kristin; Persson, Egon; Valcarce, Carmen; Astermark, Jan; Drakenberg, Torbjörn; Selander, Maria; Linse, Sara; Björk, Ingemar

doi:10.1111/j.1749-6632.1991.tb43688.x

Cited by 20 publications

(28 citation statements)

References 87 publications

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“…The shortest transcript, humbug, which is also known as junctate, encodes a highly charged protein with no known catalytic function (Dinchuk et al, 2000). Full-length BAH protein catalyzes the addition of hydroxyl groups to particular Asp or Asn residues within cEGF domains of numerous proteins, including clotting factors, Notch and its ligands, and a variety of other biologically important molecules (Rebay et al, 1991;Stenflo, 1991;Downing et al, 1996;Goruppi et al, 1997). The function(s) of this hydroxylation has not yet been defined, although the fact that some of these motifs are involved in protein-protein interaction has raised the possibility that hydroxylation may modulate certain receptor-ligand interactions (Monkovic et al, 1992;Lavaissiere et al, 1996).…”

mentioning

confidence: 99%

Antisense Oligonucleotides Selectively Regulate Aspartyl β-Hydroxylase and Its Truncated Protein Isoform in Vitro but Distribute Poorly into A549 Tumors in Vivo

Scully²,

Krauthauser³

et al. 2002

The Journal of Pharmacology and Experimental Therapeutics

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Alternative splicing of the human ␤-aspartyl (asparaginyl) hydroxylase (BAH) gene results in the expression of humbug, a truncated form of BAH that lacks the catalytic domain of the enzyme. Overexpression of BAH and humbug has been associated with a variety of human cancers, and although humbug lacks enzymatic activity, it is expressed at levels comparable with that of BAH in various cancer cell lines. Phosphorothioate antisense oligonucleotides (ONs) were designed to dissect out the function of these hydroxylase protein isoforms. In A549 cells, these ONs differentially down-regulated BAH and humbug at the mRNA and protein level. Phosphorothioate ON uptake and antisense studies were conducted in parallel in nude mice bearing A549 tumor xenografts. Microscopic examination of the tumor after administration of a fluorescein-labeled ON showed strong labeling of the outer layers of the tumor connective tissue but cells within the interior of the tumor were sparsely labeled. A modest but significant effect on tumor growth was observed in animals treated with an antisense ON directed against both BAH and humbug transcripts. However, Northern analysis of tumor RNA did not indicate a down-regulation of the targeted mRNA species. These results demonstrate the successful development of antisense ONs that selectively differentiate between the closely related ␤-hydroxylase protein isoforms. However, determination of the biological function of these proteins in vivo was limited by the poor uptake properties of phosphorothioate ONs in A549 tumors.

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confidence: 99%

Antisense Oligonucleotides Selectively Regulate Aspartyl β-Hydroxylase and Its Truncated Protein Isoform in Vitro but Distribute Poorly into A549 Tumors in Vivo

Scully²,

Krauthauser³

et al. 2002

The Journal of Pharmacology and Experimental Therapeutics

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“…The exact functions of the EGF domains in four of the Vitamin K-dependent proteases (FVII, FIX, FX, and protein C) are unknown; however, they are structurally relevant in providing the correct orientation of the Gla and SP domains of these proteases as seen in the crystal structure of the FVII-tissue factor complex [Stenflo, 1991;Banner et al, 1996]. The EGF structure is most often seen as one a-helix A1 and up to four b-strands B1 to B4 [Akhavan et al, 2000;Peyvandi et al, 2000Peyvandi et al, , 2002 linked by three disulfide bridges (Fig.…”

Section: Mutations Within the Two Egf Domainsmentioning

confidence: 99%

“…3b). Tyrosine or phenylalanine must also be present at position 23 for the correct hydroxylation of Asp18 [Stenflo, 1991]. Mutations are seen at all four of these conserved positions in EGF1, most frequently at positions 18 and 23.…”

Section: Mutations Within the Two Egf Domainsmentioning

confidence: 99%

CoagMDB: a database analysis of missense mutations within four conserved domains in five vitamin K-dependent coagulation serine proteases using a text-mining tool

Saunders

Perkins

2008

Hum. Mutat.

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Communicated by John McVeyCentral repositories of mutations that combine structural, sequence, and phenotypic information in related proteins will facilitate the diagnosis and molecular understanding of diseases associated with them. Coagulation involves the sequential activation of serine proteases and regulators in order to yield stable blood clots while maintaining hemostasis. Five coagulation serine proteases-factor VII (F7), factor IX (F9), factor X (F10), protein C (PROC), and thrombin (F2)-exhibit high sequence similarities and all require vitamin K. All five of these were incorporated into an interactive database of mutations named CoagMDB (http://www.coagMDB.org; last accessed: 9 August 2007). The large number of mutations involved (especially for factor IX) and the increasing problem of out-of-date databases required the development of new database management tools. A text mining tool automatically scans full-length references to identify and extract mutations. High recall rates between 96 and 99% and precision rates of 87 to 93% were achieved. Text mining significantly reduces the time and expertise required to maintain the databases and offers a solution to the problem of locus-specific database management and upkeep. A total of 875 mutations were extracted from 1,279 literature sources. Of these, 116 correspond to Gla domains, 86 to the N-terminal EGF domain, 73 to the C-terminal EGF domain, and 477 to the serine protease domain. The combination of text mining and consensus domain structures enables mutations to be correlated with experimentally-measurable phenotypes based on either low protein levels (Type I) or reduced functional activities (Type II), respectively. A tendency for the conservation of phenotype with structural location was identified. Hum Mutat 29(3), [333][334][335][336][337][338][339][340][341][342][343][344] 2008.

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“…FXa contains the ␥-carboxyglutamic acid domain that mediates binding to PL (31). Consequently, soluble PL in the test plasma samples may bind to this domain of FXa, thus allowing aPL to bind to FXa-associated PL and to be registered falsely as the Ab against FXa.…”

Section: Presence Of Igg Anti-fxa Ab In Aps Patientsmentioning

confidence: 99%

Antibodies against the Activated Coagulation Factor X (FXa) in the Antiphospholipid Syndrome That Interfere with the FXa Inactivation by Antithrombin

Yang

Hwang

Fitzgerald

et al. 2006

The Journal of Immunology

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Antiphospholipid Ab have been shown to promote thrombosis and fetal loss in the antiphospholipid syndrome (APS). Previously, we found IgG anti-thrombin Ab in some APS patients that could interfere with inactivation of thrombin by antithrombin (AT). Considering that activated coagulation factor X (FXa) is homologous to thrombin in the catalytic domains and is also regulated primarily by AT, we hypothesized that some thrombin-reactive Ab may bind to FXa and interfere with AT inactivation of FXa. To test these hypotheses, we studied reactivity of eight patient-derived monoclonal IgG antiphospholipid Ab with FXa and the presence of IgG anti-FXa Ab in APS patients and investigated the effects of FXa-reactive mAb on AT inactivation of FXa. The results revealed that six of six thrombin-reactive IgG mAb bound to FXa and that the levels of plasma IgG anti-FXa Ab in 38 APS patients were significantly higher than those in 30 normal controls (p < 0.001). When the mean plus 3 SDs of the 30 normal controls was used as the cutoff, 5 of 38 APS patients (13.2%) had IgG anti-FXa Ab. Importantly, three of six FXa-reactive mAb significantly inhibited AT inactivation of FXa. Combined, these results indicate that anti-FXa Ab may contribute to thrombosis by interfering with the anticoagulant function of AT on FXa in some APS patients.

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Epidermal Growth Factor‐like Domains in the Vitamin K‐Dependent Clotting Factors

Cited by 20 publications

References 87 publications

Antisense Oligonucleotides Selectively Regulate Aspartyl β-Hydroxylase and Its Truncated Protein Isoform in Vitro but Distribute Poorly into A549 Tumors in Vivo

Antisense Oligonucleotides Selectively Regulate Aspartyl β-Hydroxylase and Its Truncated Protein Isoform in Vitro but Distribute Poorly into A549 Tumors in Vivo

CoagMDB: a database analysis of missense mutations within four conserved domains in five vitamin K-dependent coagulation serine proteases using a text-mining tool

Antibodies against the Activated Coagulation Factor X (FXa) in the Antiphospholipid Syndrome That Interfere with the FXa Inactivation by Antithrombin

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