Fibrinogen γ′ chain binds thrombin exosite II

Lovely, Rehana Sultana; Moaddel, M.; Farrell, David H.

doi:10.1046/j.1538-7836.2003.00027.x

Cited by 85 publications

(112 citation statements)

References 52 publications

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“…This antibody recognizes an epitope including the high-affinity binding site for thrombin and is specific for the fibrinogen ␥Ј chain. 25 We confirmed that its affinity for the carboxyterminal peptide was lost when the last 4 residues were removed 26,27 (data not shown). Plastic 96-well microtiter plates (Greiner, Alphen a/d Rijn, The Netherlands) were coated (110 L/well) with 2 g/mL mouse anti-human ␥Ј fibrinogen during overnight incubation at 4°C.…”

Section: Fibrinogen ␥ Antigen Measurementsupporting

confidence: 57%

Genetic variation in the fibrinogen gamma gene increases the risk for deep venous thrombosis by reducing plasma fibrinogen γ′ levels

Willige

Visser

Houwing-Duistermaat

et al. 2005

Blood

229

260

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We investigated the association between haplotypes of fibrinogen alpha (FGA), beta (FGB), and gamma (FGG), total fibrinogen levels, fibrinogen ␥ (␥A/␥ plus ␥/␥) levels, and risk for deep venous thrombosis. In a population-based case-control study, the Leiden Thrombophilia Study, we typed 15 haplotype-tagging single nucleotide polymorphisms (htSNPs) in this gene cluster. None of these haplotypes was associated with total fibrinogen levels. In each gene, one haplotype increased the thrombosis risk approximately 2-fold. After adjustment for linkage disequilibrium between the genes, only FGG-H2 homozygosity remained associated with risk (odds ratio [OR], 2.4; 95% confidence interval [95% CI], 1.5-3.9). FGG-H2 was also associated with reduced fibrinogen ␥ levels and reduced ratios of fibrinogen ␥ to total fibrinogen. Multivariate analysis showed that reduced fibrinogen ␥ levels and elevated total fibrinogen levels were both associated with an increased risk for thrombosis, even after adjustment for FGG-H2. A reduced fibrinogen ␥ to total fibrinogen ratio (less than 0.69) also increased the risk (OR, 2.4; 95% CI, 1.7-3.5)

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Section: Fibrinogen ␥ Antigen Measurementsupporting

confidence: 57%

Genetic variation in the fibrinogen gamma gene increases the risk for deep venous thrombosis by reducing plasma fibrinogen γ′ levels

Willige

Visser

Houwing-Duistermaat

et al. 2005

Blood

229

260

View full text Add to dashboard Cite

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“…A 20-amino acid analog of the COOH terminus of the ␥Ј-chain of fibrinogen, ␥Ј-peptide (VRPEHPAETEYDSLYPEDDL), was prepared by Bachem Bioscience, Inc. (King of Prussia, PA), and a sheep antibody against this peptide was from Affinity Biologicals (Ancaster, ON). The two Tyr residues within the ␥Ј-peptide were modified with phosphate groups in place of sulfate to enhance stability (22). The ␥Ј-peptide-directed IgG was subjected to affinity chromatography using immobilized ␥Ј-peptide (SulfoLink Immobilization Kit for Peptides, Thermo Scientific, Rockford, IL).…”

Section: Methodsmentioning

confidence: 99%

Histidine-rich Glycoprotein Binds Fibrin(ogen) with High Affinity and Competes with Thrombin for Binding to the γ′-Chain

Stafford

Leslie

et al. 2011

Journal of Biological Chemistry

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Histidine-rich glycoprotein (HRG) is an abundant protein that binds fibrinogen and other plasma proteins in a Zn2؉ -dependent fashion but whose function is unclear. HRG has antimicrobial activity, and its incorporation into fibrin clots facilitates bacterial entrapment and killing and promotes inflammation. Although these findings suggest that HRG contributes to innate immunity and inflammation, little is known about the HRGfibrin(ogen) interaction. By immunoassay, HRG-fibrinogen complexes were detected in Zn 2؉ -supplemented human plasma, a finding consistent with a high affinity interaction. Fibrinogen is the soluble precursor of fibrin, a critical component of blood clots that endows them with strength and elasticity. Fibrinogen is a glycoprotein composed of three pairs of polypeptide chains, termed A␣, B␤, and ␥, that are connected by disulfide bonds (1). Approximately 10 -15% of circulating fibrinogen has a variant ␥-chain termed the ␥Ј-chain, which results from differential processing of the ␥ A -chain mRNA transcript (2-4). The ␥Ј-chain is distinguished from the ␥ A -chain by the presence of an acidic 20-residue extension at its COOH terminus (2, 5).Thrombin catalyzes the conversion of fibrinogen to insoluble fibrin, and during this process some thrombin remains bound to the fibrin network (6). Exosites 1 and 2 are two regulatory domains that flank the active site of thrombin and mediate its binding to fibrin (7,8). Exosite 1 of thrombin interacts with the central E-domain of fibrin, whereas exosite 2 binds only to the COOH terminus of the ␥Ј-chain. Consequently, thrombin binds ␥ A /␥ A -fibrin in a univalent fashion with a K d value of 2-4 M. In contrast, both exosites are engaged when thrombin binds to ␥ A /␥Ј-fibrin, resulting in a higher affinity interaction (K d value of 0.08 -0.18 M) (5, 9). Fibrin-bound thrombin remains active, and the protease is protected from inhibition by fluid-phase inhibitors, such as antithrombin and heparin cofactor II (6). Because of its bivalent interaction with ␥ A /␥Ј-fibrin, thrombin bound to ␥ A /␥Ј-fibrin is more protected from inhibition by fluid-phase inhibitors than thrombin bound to ␥ A /␥ Afibrin (10).Like thrombin, histidine-rich glycoprotein (HRG) 3 binds to fibrinogen and is incorporated into fibrin clots (11). Although the plasma concentration of HRG ranges from 1.6 to 2 M, the concentration in platelet-rich thrombi may be higher because HRG is stored in the alpha granules of platelets and is released when platelets are activated (12, 13). A 75-kDa glycoprotein, HRG, is composed of two NH 2 -terminal cystatin-like domains, a central histidine-rich region (HRR) flanked by two prolinerich regions, and a COOH-terminal domain (14). In addition to fibrinogen, HRG also binds plasminogen, heparan sulfate, and divalent cations, such as Zn 2ϩ (12,15,16). Therefore, HRG is hypothesized to be an important accessory or adapter protein that brings different ligands together under specific conditions (14).HRG-deficient mice exhibit a shorter prothrombin time and accelerat...

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“…Thrombin exosite II (residues encompassing R93, K236, K240, R101, and R233 19 ) binds to the ␥Ј chain with high affinity (K d value 0.20 M). 12,20 However, the highest affinity interaction occurs when both thrombin exosite I (residues encompassing K36, H71, R73, R75, Y76, R77a, and K109/110 19 ) and II bind the fibrin(ogen) E region and ␥Ј chain simultaneously (Kd values of 107 Ϯ 36 nM and 1.5 M for the high-and low-affinity binding sites, respectively). 21 Residues A414 to L427 of the ␥Ј chain have been reported to play a central role in thrombin binding because of the overall negative charge, and sulfation of residues Y418 and Y422 further enhances binding by increasing the net charge.…”

Section: Thrombin Bindingmentioning

confidence: 99%