Location of the binding site “b” for lateral polymerization of fibrin

Hasegawa, Noboru; Sasaki, Susumu

doi:10.1016/0049-3848(90)90318-7

Cited by 58 publications

(52 citation statements)

References 13 publications

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“…The latter explanation is in agreement with the observation that inhibition of fibrin polymerization reduces the acceleratory effect of fibrin on t-PA-induced plasminogen activation (40)(41)(42)(43). Further evidence for this hypothesis is presented by Mirshahi et al (44) who showed that fibrin formed from low-Mr fibrinogen, which results in reduced lateral association (10), is more resistant to fibrinolysis induced by t-PA than fibrin prepared from high-Mr fibrinogen.…”

Section: Discussionmentioning

confidence: 84%

“…Fibril formation is predominantly due to interaction between the A and a sites (4); interaction between B and b sites contributes to lateral fibril association and augment thick fiber formation (4,9). It has recently been suggested that the carboxyl-terminal region of the Aa chain constitutes an important component of the b polymerization site in fibrinogen ( 10).…”

Section: Introductionmentioning

confidence: 99%

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Molecular basis for fibrinogen Dusart (A alpha 554 Arg-->Cys) and its association with abnormal fibrin polymerization and thrombophilia.

Koopman

Haverkate²,

Grimbergen³

et al. 1993

J. Clin. Invest.

111

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The molecular defect in the abnormal fibrinogen Dusart (Paris V) that is associated with thrombophilia was determined by sequence analysis of genomic DNA that had been amplified using the polymerase chain reaction. The propositus was heterozygous for a single base change (C -> T) in the Aa-chain gene, resulting in the amino acid substitution Aa 554 Arg Cys. Restriction analysis of the amplified DNA derived from the family members showed that his father and his two sons were also heterozygous. Electron microscopic studies on fibrin formed from purified fibrinogen Dusart demonstrated fibers that were much thinner than in normal fibrin. In contrast to the previously observed defective binding of plasminogen, the binding of thrombospondin to immobilized fibrinogen Dusart was similar to that of normal fibrinogen. Immunoblot analysis of plasma fibrinogen demonstrated that a substantial part of the fibrinogen Dusart molecules were disulfide-linked to albumin. The plasma of the affected family members also contained fibrinogen-albumin complexes. Furthermore, small amounts of high molecular weight complexes containing fibrinogen were detected in all the heterozygous individuals. These data indicate that the molecular abnormality in fibrinogen Dusart (Aa 554 Arg -n Cys) results in defective lateral association of the fibrin fibers and disulfide-linked complex formation with albumin, and is associated with a family history of recurrent thrombosis in the affected individuals. (J. Clin. Invest. 1993.

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Section: Discussionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Molecular basis for fibrinogen Dusart (A alpha 554 Arg-->Cys) and its association with abnormal fibrin polymerization and thrombophilia.

Koopman

Haverkate²,

Grimbergen³

et al. 1993

J. Clin. Invest.

111

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“…Thrombin converts fibrinogen to its active form, fibrin monomer, by cleaving fibrinopeptides A and B from the N-termini of the Aa and Bb chains, a process that exposes polymerization sites which then interact with preformed complementary sites located at the C-termini of the b and g chains (Kudryk et al, 1974;Hasegawa & Sasaki, 1990;Olexa & Budzynski, 1980). This spontaneous self-assembly process culminates in the production of the three-dimensional fibrin lattice which forms the haemostatic plug (Hantgan & Herman, 1979).…”

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confidence: 99%

Fibrinogen Otago: a major α chain truncation associated with severe hypofibrinogenaemia and recurrent miscarriage

et al. 1997

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Summary.A woman with a preliminary diagnosis of afibrinogenaemia was later found to have a functional fibrinogen of 0 . 06 mg/ml and markedly prolonged thrombin and reptilase times. The stoichiometry of fibrinopeptide release was normal but there was a gross delay in the polymerization of purified fibrin. Plasma protein electrophoresis showed an absence of normal fibrinogen and a novel anodal component which was confirmed as fibrinogen by immunofixation. Western blots of non-reducing SDS-PAGE gels indicated a molecular weight of 270 kD, compared to 340 kD for normal fibrinogen and similar analysis of reducing gels showed that the expected 67 kD Aa chain was missing and replaced by a 30 kD band. This aberrant chain was not detected by the monoclonal antibody F-103, which recognizes the epitope formed by residues 259-276 of the Aa chain. Cycle sequencing of the DNA encoding the F-103 epitope revealed the homozygous insertion of cytosine at position 4133 of the gene sequence. Predictably this translates as three new amino acids ( 268 Gln-Glu-Pro) before termination at a new (TAG) stop codon. No abnormal Aa chains could be detected in plasma from the woman's heterozygous son. The hypofibrinogenaemia observed is likely to be the result of diminished assembly and/or secretion of the truncated Aa chains rather than enhanced extracellular degradation.

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“…During blood coagulation, fibrinogen is converted to an insoluble fibrin clot by the serine protease thrombin, which cleaves four peptide bonds, releasing two fibrinopeptides A (FpA, A␣ 1-16) and two fibrinopeptides B (FpB, B␤ [1][2][3][4][5][6][7][8][9][10][11][12][13][14] and fibrin monomers that polymerize spontaneously. The association of fibrin monomers into a fibrin clot has long been described as a two-step process, where the first step involves half-staggered, end-to-end interactions leading to doublestranded protofibrils and the second step, usually called lateral aggregation, involves the assembly of protofibrils into thick, multi-stranded fibers that branch to form a fibrin network.…”

mentioning

confidence: 99%

Severely Impaired Polymerization of Recombinant Fibrinogen γ-364 Asp → His, the Substitution Discovered in a Heterozygous Individual

Okumura

Gorkun

Lord

1997

Journal of Biological Chemistry

104

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During blood coagulation, soluble fibrinogen is converted to fibrin monomers that polymerize to form an insoluble clot. Polymerization has been described as a two-step process: the formation of double-stranded protofibrils and the subsequent lateral aggregation of protofibrils into fibers. Previous studies have shown that ␥ chain residues Tyr-363 and Asp-364 have a significant role in polymerization, most likely in protofibril formation. To better define the role of these residues, we synthesized three fibrinogens with single substitutions at these two positions: Tyr-363 3 Ala, Asp-364 3 Ala, and Asp-364 3 His. We found that the release of fibrinopeptides A and B was the same for these variants and normal recombinant fibrinogen, showing that all variants had normal fibrin formation. In contrast, we found that polymerization was significantly delayed for both Ala variants and was almost nonexistent for the His variant. Clottability for the Ala variants was only slightly reduced, and fibrin gels were formed. Surprisingly, clottability of the His variant was substantially reduced, and fibrin gels were not formed. Our data suggest that both protofibril formation and lateral aggregation were altered by these substitutions, indicating that the C-terminal domain of the ␥ chain has a role in both polymerization steps.

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Location of the binding site “b” for lateral polymerization of fibrin

Cited by 58 publications

References 13 publications

Molecular basis for fibrinogen Dusart (A alpha 554 Arg-->Cys) and its association with abnormal fibrin polymerization and thrombophilia.

Molecular basis for fibrinogen Dusart (A alpha 554 Arg-->Cys) and its association with abnormal fibrin polymerization and thrombophilia.

Fibrinogen Otago: a major α chain truncation associated with severe hypofibrinogenaemia and recurrent miscarriage

Severely Impaired Polymerization of Recombinant Fibrinogen γ-364 Asp → His, the Substitution Discovered in a Heterozygous Individual

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