Cross-Linked Fibrinogen Dimers Demonstrate a Feature of the Molecular Packing in Fibrin Fibers

Fowler, Walter E.; Erickson, H P; Hantgan, RR; McDonagh, Jan; Hermans, Jan

doi:10.1126/science.6108612

Cited by 67 publications

(48 citation statements)

References 6 publications

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“…Some studies suggested that the isopeptide bond was formed between 2 fibrin molecules aligned end to end in the same strand of the protofibril, 53,55 while others suggested that the ␥-␥ cross-link was oriented between 2 fibrin molecules aligned across the fibrin protofibril in a transorientation. 56,57 Recent crystallography data of the cross-linked D-fragment indicate that the predominant orientation is the cisconfiguration.…”

Section: Substrates Of Factor Xiiia and Biological Consequences Of Crmentioning

confidence: 99%

Role of factor XIII in fibrin clot formation and effects of genetic polymorphisms

Ariëns

Lai

Weisel

et al. 2002

Blood

327

272

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Factor XIII and fibrinogen are unusual among clotting factors in that neither is a serine protease. Fibrin is the main protein constituent of the blood clot, which is stabilized by factor XIIIa through an amide or isopeptide bond that ligates adjacent fibrin monomers. Many of the structural and functional features of factor XIII and fibrin(ogen) have been elucidated by protein and gene analysis, site-directed mutagenesis, and x-ray crystallography. However, some of the molecular aspects involved in the complex processes of insoluble fibrin formation in vivo and in vitro remain unresolved. The findings of a relationship between fibrinogen, factor XIII, and cardiovascular or other thrombotic disorders have focused much attention on these 2 proteins. Of particular interest are associations between common variations in the genes of factor XIII and altered risk profiles for thrombosis. Although there is much debate regarding these observations, the implications for our understanding of clot formation and therapeutic intervention may be of major importance. In this review, we have summarized recent findings on the structure and function of factor XIII. This is followed by a review of the effects of genetic polymorphisms on protein structure/function and their relationship to disease. (Blood. 2002;100:743-754)

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Section: Substrates Of Factor Xiiia and Biological Consequences Of Crmentioning

confidence: 99%

Role of factor XIII in fibrin clot formation and effects of genetic polymorphisms

Ariëns

Lai

Weisel

et al. 2002

Blood

327

272

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“…Since the report by Fowler et al (20), which involved electron microscopic observations on crosslinked fibrinogen dimers, it has been commonly held that the C-terminal ␥ chain crosslinking sequences in fibrin are situated at the extreme end of each molecule, bridging directly between end-to-end abutted fibrin molecules in a so-called ''DD-long'' arrangement. Recently, the ''end-to-end'' crosslinking idea received somewhat revised support from studies of crystals of crosslinked D dimer fragments (21), in which crosslinked C-terminal ␥ chains, though not situated at the extreme end of the molecule as originally envisioned, were inferred nevertheless to traverse the abutting D domains in an end-to-end alignment.…”

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confidence: 99%

“…However, several independent lines of evidence, beginning with reports by Selmayr et al (22,23), have indicated that the crosslinked ␥ chain segments in fibrin do not straddle the ends of adjacent D domains but rather tend to extend transversely between each fibril strand (1,(24)(25)(26). Evidence in favor of the transverse bond arrangement includes among the above cited articles, the electron microscopic demonstration of double-stranded crosslinked fibrinogen fibrils, visualization of bridging filaments representing transversely positioned ␥ chains within crosslinked fibrinogen fibrils (1) and in crosslinked D-fibrin-D complexes (26), and evidence indicating that the abutting ends of fibrin D domains where end-to-end intermolecular contacts are now recognized to occur (the so-called D:D site) (1,21,25), do not as first proposed (20), contain the C-terminal ␥ chain segment. Crystallographic analyses of D domain structures (21,27) have amply confirmed the last conclusion by showing that the C-terminal region of the ␥ chain emerges from the middle of the ␥ chain segment of the D domain 3.5 nm from its extreme end (Fig.…”

mentioning

confidence: 99%

The location of the carboxy-terminal region of γ chains in fibrinogen and fibrin D domains

Mosesson

Siebenlist

Meh

et al. 1998

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

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Fibrinogen molecules are Ϸ45 nm in length and are comprised of three major globular domains. There are two outer D domains, each connected by a ''coiled-coil'' region to the central E domain, within which the halves of each molecule are joined by disulfide bridges (Fig. 1). This article is concerned with precisely locating the carboxy-terminal segment of the ␥ chain, a region termed ''␥ XL '', that comprises one of several self-association sites in fibrinogen D domains (1). The ␥ XL sequence contains one factor XIIIa amine donor͞acceptor-crosslinking site between ␥406K and ␥398Q or ␥399Q [␥398͞ 399Q] (2-4), as well as an overlapping platelet fibrinogen receptor-binding site lying between ␥400 and ␥411 (5).To approach our objective, we prepared fibrinogen into which thioacetyl cadaverine amine donors had been covalently incorporated at glutamine acceptor sites in the presence of factor XIIIa (plasma transglutaminase) (Fig. 2). Subsequently, we labeled the thiol group on the cadaverine with an electron dense thiol-specific gold-cluster compound, undecagoldmonoaminopropyl maleimide (Au 11 ) (6). Au 11 -cadaverinelabeled fibrinogen was then examined by high resolutionscanning transmission electron microscopy (STEM) (7) to locate the Au 11 clusters that had been covalently attached at the amine acceptor site (␥398͞399Q) in the D domain. The relatively small diameter (0.8 nm) of the Au 11 cluster (6) provides a discriminating ultrastructural probe for pinpointing its position in the fibrinogen molecule. Gold cluster labeling has been applied to several proteins or nucleic acids for topographical molecular mapping of specific binding sites or domains (7-11 inter alia) and in particular has been used to determine precisely the location as well as the orientation of the amino terminal portions of the two A␣ chains within each fibrinogen E domain (12).The C-terminal region of each ␥ chain contains a single crosslinking site at which factor XIIIa catalyzes the formation of ␥ dimers (1, 13, 14) by incorporating intermolecular reciprocal -(␥-glutamyl) lysine bridges between a donor ␥406 lysine of one chain and a glutamine acceptor at ␥398͞399 of another (2-4). ␥ chain crosslinking occurs solely between these residues (2-4, 15, 16), whereas there are several amine donor lysine and amine acceptor glutamine sites in A␣ chains (16,17). Primary amine compounds like cadaverine are competitive amine donor substrates that become specifically incorporated in the presence of factor XIIIa at the single ␥ chain acceptor site or at one or more ␣ chain acceptor sites (2-4, 15, 18, 19).Noncovalent interaction between D and E domains in an assembling fibrin polymer facilitates the antiparallel intermolecular alignment of ␥ chain pairs in D domains, thereby accelerating the rate at which factor XIIIa-catalyzed crosslinking occurs at ␥ XL sites (1,14). Since the report by Fowler et al. (20), which involved electron microscopic observations on crosslinked fibrinogen dimers, it has been commonly held that the C-terminal ␥ chain crossl...

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“…3 Fibrin monomers then bind to one another in an overlapping manner to form 2 molecule thick protofibrils ( Figure 1). 4,5 Plasma remains fluid until 25% to 30% of plasma fibrinogen is cleaved by thrombin, 6 allowing time for fibrin to polymerize while simultaneously promoting thrombin activation of plasma factor XIII. 7 Thrombin remains associated with fibrin, 8 and as additional fibrin molecules polymerize, it activates plasma factor XIII bound to fibrinogen.…”

Section: Introductionmentioning

confidence: 99%

D-dimer antigen: current concepts and future prospects

Adam

Key

Greenberg

2009

Blood

528

453

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The D-dimer antigen is a unique marker of fibrin degradation that is formed by the sequential action of 3 enzymes: thrombin, factor XIIIa, and plasmin. First, thrombin cleaves fibrinogen producing fibrin monomers, which polymerize and serve as a template for factor XIIIa and plasmin formation. Second, thrombin activates plasma factor XIII bound to fibrin polymers to produce the active transglutaminase, factor XIIIa. Factor XIIIa catalyzes the formation of covalent bonds between D-domains in the polymerized fibrin. Finally, plasmin degrades the crosslinked fibrin to release fibrin degradation products and expose the D-dimer antigen. D-dimer antigen can exist on fibrin degradation products derived from soluble fibrin before its incorporation into a fibrin gel, or after the fibrin clot has IntroductionFibrinogen is a soluble plasma glycoprotein that is transformed into highly self-adhesive fibrin monomers after thrombin cleavage. 1 A detailed overview of the process of fibrin formation was recently published. 2 In brief, in the first step of D-dimer formation, thrombin cleavage exposes a previously cryptic polymerization site on fibrinogen that promotes the binding of either another fibrinogen or a monomeric fibrin molecule. 3 Fibrin monomers then bind to one another in an overlapping manner to form 2 molecule thick protofibrils ( Figure 1). 4,5 Plasma remains fluid until 25% to 30% of plasma fibrinogen is cleaved by thrombin, 6 allowing time for fibrin to polymerize while simultaneously promoting thrombin activation of plasma factor XIII. 7 Thrombin remains associated with fibrin, 8 and as additional fibrin molecules polymerize, it activates plasma factor XIII bound to fibrinogen. 9 The complex between soluble fibrin polymers, thrombin, and plasma factor XIII promotes the formation of factor XIIIa before a fibrin gel is detected. 6 In the second step of D-dimer formation, factor XIIIa covalently cross links fibrin monomers via intermolecular isopeptide bonds formed between lysine and glutamine residues within the soluble protofibrils and the insoluble fibrin gel. 10 D-dimer antigen remains undetectable until it is released from crosslinked fibrin by the action of plasmin. In the final step of D-dimer formation, plasmin formed on the fibrin surface by plasminogen activation cleaves substrate fibrin at specific sites ( Figure 1). 11 Fibrin degradation products are produced in a wide variety of molecular weights, including the terminal degradation products of crosslinked fibrin containing D-dimer and fragment E complex (Figure 1). 12,13 It is uncommon to detect circulating terminal fibrin degradation products (D-dimer-E complex) in human plasma, whereas soluble high-molecular-weight fragments that contain the "D-dimer antigen" are present in patients with DIC and other thrombotic disorders. 14 These fragments may be derived from soluble fibrin before it has been incorporated into a fibrin gel, or alternatively may be derived from high-molecular-weight complexes released from an insoluble clot (Figure 2). 15,16 "D-...

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Cross-Linked Fibrinogen Dimers Demonstrate a Feature of the Molecular Packing in Fibrin Fibers

Cited by 67 publications

References 6 publications

Role of factor XIII in fibrin clot formation and effects of genetic polymorphisms

Role of factor XIII in fibrin clot formation and effects of genetic polymorphisms

The location of the carboxy-terminal region of γ chains in fibrinogen and fibrin D domains

D-dimer antigen: current concepts and future prospects

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