Anticoagulant function of a 24-Kd fragment isolated from human fibrinogen A alpha chains

Lau, HK

doi:10.1182/blood.v81.12.3277.bloodjournal81123277

Cited by 2 publications

(2 citation statements)

References 1 publication

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“…More direct evidence comes from studies of monoclonal antibodies specific for particular regions of the aC domains (Cierniewski & Budzynski, 1992). In addition, results of a very recent study using a 24-kDa fragment isolated from the carboxyl terminal Aa chain (Lau, 1993) are also consistent with the conclusions presented here. It is important to note that the aC domains are not required for lateral aggregation, which can occur when they are completely missing in fragment X2 monomer, but only promote it.…”

Section: Discussionsupporting

confidence: 85%

Role of the .alpha.C Domains of Fibrin in Clot Formation

Gorkun¹,

Veklich²,

Medved³

et al. 1994

Biochemistry

184

240

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The role of the carboxyl-terminal portion of the alpha chains of fibrin (alpha C domains) in clot formation was investigated by transmission and scanning electron microscopy and turbidity studies of clots made from preparations of molecules missing one or both of these domains. Highly purified and entirely clottable preparations of bovine fragment X monomer, one containing primarily molecules missing a single alpha C domain (fragment X1) and the other consisting of molecules missing both alpha C domains (fragment X2), were used for these experiments. These preparations were characterized by various methods, including the complete determination of the amino- and carboxyl-termini of all peptides and fragments. These preparations formed clots on dilution to neutral pH. In all cases, clots observed by either scanning or transmission electron microscopy were made up of a branched network of fibers, similar to those formed by thrombin treatment of intact fibrinogen, suggesting that the alpha C domains are not necessary for protofibril and fiber formation or branching. However, both the fiber and clot structure varied with the different fractions, indicating that the alpha C domains do participate in polymerization. The rate of assembly, as indicated by the lag period and maximum rate of turbidity increase, as well as the final turbidity, was decreased with removal of the alpha C domains, suggesting that they accelerate polymerization. preparations of isolated alpha C fragment added to fibrin monomer have striking effects on the turbidity curves, showing a decrease in the rate of polymerization in a dose-dependent manner but not complete inhibition. Electron microscopy of fibrin monomer desA molecules at neutral pH showed that most of the alpha C domains, like those in fibrinogen, remain associated with the central region. Thus, it appears that normally with thrombin cleavage of fibrinogen the effects of the interactions of alpha C domains observed here will be most significant for lateral aggregation.

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Section: Discussionsupporting

confidence: 85%

Role of the .alpha.C Domains of Fibrin in Clot Formation

Gorkun¹,

Veklich²,

Medved³

et al. 1994

Biochemistry

184

240

View full text Add to dashboard Cite

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“…(i) Clot formation is slowed, and the clot structure is perturbed when RC regions are removed from fibrinogen either proteolytically (15)(16)(17)(18)(19) or as a result of a natural and/or artificial genetic defect (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). (ii) Isolated RC fragments (19,33,34) or RC-specific antibodies (35,36) interfere with clot formation. (iii) RC regions polymerize and can be cross-linked by factor XIIIa, thus contributing to clot stability (33,(37)(38)(39)(40).…”

mentioning

confidence: 99%

Direct Evidence for Specific Interactions of the Fibrinogen αC-Domains with the Central E Region and with Each Other

et al. 2007

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The carboxyl-terminal regions of the fibrinogen Aα chains (αC regions) form compact αC-domains tethered to the bulk of the molecule with flexible αC-connectors. It was hypothesized that in fibrinogen two αC-domains interact intramolecularly with each other and with the central E region preferentially through its N-termini of Bβ chains, and that removal of fibrinopeptides A and B upon fibrin assembly results in dissociation of the αC regions and their switch to intermolecular interactions. To test this hypothesis, we studied the interactions of the recombinant αC region (Aα221-610 fragment) and its sub-fragments, αC-connector (Aα221-391) and αC-domain (Aα392-610), between each other and with the recombinant (Bβ1-66) 2 and (β15-66) 2 fragments and NDSK corresponding to the fibrin(ogen) central E region, using laser tweezers-based force spectroscopy. TheαC-domain, but not the αC-connector, bound to NDSK, which contains fibrinopeptides A and B, and less frequently to desA-NDSK and (Bβ1-66) 2 containing only fibrinopeptides B; it was poorly reactive with desAB-NDSK and (β15-66) 2 both lacking fibrinopeptides B. The interactions of the αC-domains with each other and with the αC-connector were also observed, although they were weaker and heterogeneous in strength. These results provide the first direct evidence for the interaction between the αC-domains and the central E region through fibrinopeptides B, in agreement with the above hypothesis, and indicate that fibrinopeptides A are also involved. They also confirm the hypothesized homomeric interactions between the αC-domains and display their interaction with the αC-connectors, which may contribute to covalent cross-linking of α polymers in fibrin. KeywordsBlood coagulation; protein interactions; fibrinogen; fibrin Fibrinogen is a blood plasma protein involved in a number of (patho)physiological processes such as hemostasis, fibrinolysis, inflammation, angiogenesis, wound healing, and neoplasia *To whom correspondence should be addressed: Dr. Rustem I. Litvinov, Department of Cell and Developmental Biology, University of Pennsylvania, School of Medicine, 421 Curie Blvd., 1040 BRB II/III, Philadelphia, PA 19104-6058, USA. Tel.: 215-898-9141; Fax: 215-898- NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript (1,2). This polyfunctionality is due to the complex structure of fibrinogen molecules that have multiple binding sites, either constitutively open or exposed after precise enzymatic cleavage and/or conformational rearrangement. The ability to polymerize upon the action of thrombin is the unique property of fibrinogen that mainly determines its physiological significance.Structurally, fibrinogen is a 45 nm-long elongated dimer composed of three pairs of nonidentical polypeptide chains, designated Aα, Bβ, and γ (Fig. 1). The N-termini of the six chains, cross-linked by a cluster of disulfide bonds, form a central part, hence named "N-terminal disulfide knot" (3). The C-termini of Bβ and γ chains form globular modules on each end of the ...

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Anticoagulant function of a 24-Kd fragment isolated from human fibrinogen A alpha chains

Cited by 2 publications

References 1 publication

Role of the .alpha.C Domains of Fibrin in Clot Formation

Role of the .alpha.C Domains of Fibrin in Clot Formation

Direct Evidence for Specific Interactions of the Fibrinogen αC-Domains with the Central E Region and with Each Other

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