An Abnormal Fibrinogen Fukuoka II (Gly-Bβ 15 → Cys) Characterized by Defective Fibrin Lateral Association and Mixed Disulfide Formation

Kamura, Takumi; Tsuda, Hiroko; Yae, Yoshiaki; Hattori, Sachiko; Ohga, Shouichi; Shibata, Yosaburo; Kawabata, Shun-ichiro

doi:10.1074/jbc.270.49.29392

Cited by 17 publications

(28 citation statements)

References 36 publications

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“…13,14 Reptilase-catalyzed polymerization of several dysfibrinogens, including B␤Arg14Cys and B␤Gly15Cys, 15-17 also shows impaired desA polymerization. Taken together, these results suggest that the N-termini of the B␤ chains [13][14][15][16][17] and residues in the ␥C domains of growing protofibrils 10 participate in desA polymerization.…”

Section: Introductionmentioning

confidence: 83%

Recombinant BβArg14His fibrinogen implies participation of N-terminus of Bβ chain in desA fibrin polymerization

Moen

Gorkun²,

Weisel³

et al. 2003

Blood

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We synthesized B␤Arg14His fibrinogen with histidine substituted for arginine at the B␤ thrombin-cleavage site. This substitution led to a 300-fold decrease in the rate of thrombin-catalyzed fibrinopeptide B (FpB, B␤1-14) release, whereas the rate of FpA release was normal with either thrombin or the FpA-specific enzyme, batroxobin. Both thrombin-and batroxobincatalyzed polymerization of B␤Arg14His fibrinogen were significantly impaired, with a longer lag time, slower rate of lateral aggregation, and decreased final turbidity. Moreover, desA monomer polymerization was similarly impaired, demonstrating that the histidine substitution itself, and not the lack of FpB cleavage, caused the abnormal polymerization of B␤Arg14His fibrin. Scanning electron microscopy showed B␤Arg14His fibrin fibers were thinner than normal (B␤Arg14His, approximately 70 nm; normal, approximately 100 nm; P < .0001), as expected from the decreased final turbidity. We conclude that the N-terminus of the B␤ chain is involved in the lateral aggregation of normal desA protofibrils and that the Arg3His substitution disrupts these interactions in B␤Arg14His fibrinogen. (Blood. 2003;102:2466-2471)

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Section: Introductionmentioning

confidence: 83%

Recombinant BβArg14His fibrinogen implies participation of N-terminus of Bβ chain in desA fibrin polymerization

Moen

Gorkun²,

Weisel³

et al. 2003

Blood

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“…Remarkably, although neo-Cys residues have been identified in all 3 chains, all abnormal fibrinogens to date with intermolecular, disulfide-bridged fibrinogen molecules have neo-Cys located in the B␤ chain. The neo-Cys residues in fibrinogens Fukuoka 28 and IJmuiden 29 are located in the N-terminal end of the B␤ chain, whereas in Osaka VI 30 the neo-Cys is in the C-terminal end. Perhaps there is a feature of chain assembly that permits formation of intermolecular disulfides through the B␤ chains but not through the A␣ or ␥ chains.…”

Section: Discussionmentioning

confidence: 99%

The impaired polymerization of fibrinogen Longmont (Bβ166Arg→Cys) is not improved by removal of disulfide-linked dimers from a mixture of dimers and cysteine-linked monomers

Lounes

Lefkowitz

Henschen-Edman

et al. 2001

Blood

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This study identified a new substitution in the B␤ chain of an abnormal fibrinogen, denoted Longmont, where the residue Arg166 was changed to Cys. The variant was discovered in a young woman with an episode of severe hemorrhage at childbirth and a subsequent mild bleeding disorder. The neo-Cys residues were always found to be disulfide-bridged to either an isolated Cys amino acid or to the corresponding Cys residue of another abnormal fibrinogen molecule, forming dimers. Removing the dimeric molecules using gel filtration did not correct the fibrin polymerization defect. Fibrinogen Longmont had normal fibrinopeptide A and B release and a functional polymerization site "a." Thus, the sites "A" and "a" can interact to form protofibrils, as evidenced by dynamic light-scattering measurements. These protofibrils, however, were unable to associate in the normal manner of lateral aggregation, leading to abnormal clot formation, as shown by an impaired increase in turbidity. Therefore, it is concluded that the substitution of Arg1663Cys-Cys alters fibrinogen Longmont polymerization by disrupting interactions that are critical for normal lateral association of protofibrils. IntroductionThe fibrinogen molecule is composed of 2 copies of 3 polypeptide chains called A␣, B␤, and ␥. The molecule consists of a central domain (E) linked to 2 distal domains (D) by a coiled-coil connector. The N-terminal ends of the 6 chains form the E domain, whereas the C-terminal parts of the ␥ and B␤ chains and a short fragment of the C-terminal domain of the A␣ chain constitute the D domain.The fibrinogen-to-fibrin conversion is an ordered reaction. It is initiated by the cleavage of fibrinopeptides A and B (FpA and FpB) by thrombin, which unmasks polymerization sites "A" and "B" in the neo-N-terminal ends of the ␣ and ␤ chains, respectively. 1 Thereafter, the fibrin monomers interact spontaneously and form a fibrin clot. Concomitantly, thrombin-activated factor XIII stabilizes the clot by introducing interchain cross-links between ␥ chains and between ␣ chains. [2][3][4] Fibrin polymerization is a 2-step process. First, half-staggered, end-to-end interactions form double-stranded protofibrils, which result from interactions between site "A" and its complementary site "a," 5 always present in the ␥ chain part of the D domain. 6 In fact, the peptide Gly-Pro-Arg-Pro (GPRP), which resembles the natural Gly-Pro-Arg-Val sequence of the N-terminus extremity of the ␣ chain depleted in FpA, prevents clot formation. 7 In the second step, termed "lateral association," the protofibrils are assembled into thick fibers of fibrin that branch to form a fibrin network. 8,9 The interactions involved in the lateral association are less well characterized. It has been proposed that the release of FpB enhances lateral association. 10,11 Alternatively, the release of FpB may be a consequence of fibrin formation. 12 Moreover, the C-terminal domains of the A␣ chain may also participate in lateral association. 13,14 In this report, we describe fibrinogen Longmont,...

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“…It is interesting that for the BArg14Cys variants, which are the immediate vicinity of BGly15 residue and with a potential albumin binding (demonstrated in the propositus of Ijmuiden [12]; however, no others have been analyzed), severe thrombosis such as deep venous thrombosis, pulmonary embolism, or cerebral infarction has been reported in 6 out of the 8 families [4, [10][11][12][13][14][15][16]. Of the four previously found heterozygous BGly15Cys variants, which were positive for the albumin binding form, only the Kosai propositus [6,7] suffered from arteriosclerosis obliterans, and no history of thrombosis was reported among the members of the Ogasa [6,7], Ise [8], or Fukuoka II [9] families.…”

Section: Discussionmentioning

confidence: 99%

“…Two identical variants have already been reported as fibrinogens Ise [8] and Fukuoka II [9]. It is interesting that no BGly15Cys variant has ever been reported outside of Japan.…”

Section: Introductionmentioning

confidence: 93%

Analysis of plasmin generation and clot lysis of plasma fibrinogen purified from a heterozygous dysfibrinogenemia, BβGly15Cys (Hamamatsu II)

Kamijyo

Hirota-Kawadobora²,

Yamauchi³

et al. 2009

Blood Coagulation &Amp; Fibrinolysis

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The H-II plasma fibrinogen showed the presence of albumin-binding variant forms, a dimeric molecule of variant fibrinogen, and impairment of lateral aggregation during fibrin polymerization. The H-II fibrin clot showed lower density of bundles and thinner diameters of fibers than in the normal fibrin clot. In the clot lysis experiments with overlaid plasmin, H-II fibrin showed a similar lysis period and lysis rate to the normal control. Moreover, plasmin generation from a mixture of thrombin, tPA, plasminogen, and H-II fibrinogen also showed a similar rate to normal fibrinogen. Although the propositus suffered an infarction, the present study did not observe delayed clot lysis; i.e., the clot was not resistant to plasmin degradation. Therefore, we did not clarify an association between the BGly15Cys dysfibrinogenemia and arterial thrombosis.3

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An Abnormal Fibrinogen Fukuoka II (Gly-Bβ 15 → Cys) Characterized by Defective Fibrin Lateral Association and Mixed Disulfide Formation

Cited by 17 publications

References 36 publications

Recombinant BβArg14His fibrinogen implies participation of N-terminus of Bβ chain in desA fibrin polymerization

Recombinant BβArg14His fibrinogen implies participation of N-terminus of Bβ chain in desA fibrin polymerization

The impaired polymerization of fibrinogen Longmont (Bβ166Arg→Cys) is not improved by removal of disulfide-linked dimers from a mixture of dimers and cysteine-linked monomers

Analysis of plasmin generation and clot lysis of plasma fibrinogen purified from a heterozygous dysfibrinogenemia, BβGly15Cys (Hamamatsu II)

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