Natively unfolded regions of the vertebrate fibrinogen molecule

Doolittle, Russell F.; Kollman, Justin M.

doi:10.1002/prot.20758

Cited by 37 publications

(53 citation statements)

References 69 publications

(75 reference statements)

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“…Many other experiments that utilized heterogeneous fibrin(ogen) degradation products or heterozygous dysfibrinogens (6) get at the αC-mediated interactions far less directly, making interpretation difficult and sometimes ambiguous. Therefore, the ability of the αC domains to form specific associations still has been a matter of debate (42). In this study, for the first time, we directly observed and quantified the bimolecular interactions between recombinant fibrin(ogen) fragments containing the Cterminal parts of the Aα chains and the N-terminal portions of the Bβ chains, thus reproducing the intramolecular associations of the αC-domains with the central part of the fibrinogen molecule and between each other.…”

Section: Discussionmentioning

confidence: 96%

“…The long-standing interest in the role of the C-terminal parts of the fibrinogen Aα chains, referred to as "αC-domains", in fibrin polymerization (6,8,(15)(16)(17)(18)(19)22,26,33,35,36,(38)(39)(40)(59)(60)(61) has led to the current notion that the αC-domains are important participants of fibrin clot formation, although this is still controversial (42). There is evidence that the αC-domains accelerate fibrin polymerization and make the ultimate clot structure more stable, stiff, and resistant to fibrinolysis (32).…”

Section: Discussionmentioning

confidence: 99%

“…Although this "intra-to intermolecular switch" hypothesis coherently accounts for the location of the αC-domains in fibrinogen and fibrin and suggests a possible mechanism for the exposure of their multiple binding sites upon conversion of fibrinogen into fibrin, it is not universally accepted (42). The major reason for the lack of consensus is that this hypothesis is based mainly on low resolution data obtained by electron microscopy.…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…Fibrinogen is a rod-shaped soluble plasma glycoprotein that plays a significant role in hemostasis and wound healing [1,2]. Its main function is the formation of three-dimensional network constructed of fibrin fibers, fibrin clot.…”

Section: Introductionmentioning

confidence: 99%

“…Its main function is the formation of three-dimensional network constructed of fibrin fibers, fibrin clot. Fibrinogen is a dimer composed of three polypeptide chains, Aα, Bβ, and γ chains, (AαBβγ) 2 . Molecular weight is 340 kDa, and the molecular length is 45 nm.…”

Section: Introductionmentioning

confidence: 99%

Effect of Plasmin Treatment on the Fibrin Gel Formation

Yatagai

Kubota

Toyama

et al. 2011

Trans. Mat. Res. Soc. Japan

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In order to clarify the effective regions that are substantially involved in the gelling process of plasma glycoprotein fibrinogen, we examined the aggregating properties of plasmin-treated fibrinogen, fragment-X. Two types of fragment-X were prepared by the digestion at 6 o C and 37 o C (fragment-XY and -XN, respectively). αC regions were cleaved thoroughly in both samples, but the amount of cleavage of BβN region differed between them (higher in the fragment-XN). Thrombin-and reptilase-catalyzed fibrin polymerizations were studied for both of the samples. Although the B-knob:b-hole interaction does neither work in the reptilase-catalyzed fibrin polymerization nor the αC-αC interaction is present, network formation proceeded in the fragment-XY with delayed polymerization. In the fragment-XN, protofibril formation occurred, but lateral aggregation did not. Mixing effect of intact fibrinogen showed that BβN region might play an important role in the lateral aggregation process cooperatively with αC-domain. .

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A Comparison of the Mechanical and Structural Properties of Fibrin Fibers with Other Protein Fibers

Guthold

Liu

Sparks

et al. 2007

Cell Biochem Biophys

201

192

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In the past few years a great deal of progress has been made in studying the mechanical and structural properties of biological protein fibers. Here, we compare and review the stiffness (Young's modulus, E) and breaking strain (also called rupture strain or extensibility, epsilon(max)) of numerous biological protein fibers in light of the recently reported mechanical properties of fibrin fibers. Emphasis is also placed on the structural features and molecular mechanisms that endow biological protein fibers with their respective mechanical properties. Generally, stiff biological protein fibers have a Young's modulus on the order of a few Gigapascal and are not very extensible (epsilon(max) < 20%). They also display a very regular arrangement of their monomeric units. Soft biological protein fibers have a Young's modulus on the order of a few Megapascal and are very extensible (epsilon(max) > 100%). These soft, extensible fibers employ a variety of molecular mechanisms, such as extending amorphous regions or unfolding protein domains, to accommodate large strains. We conclude our review by proposing a novel model of how fibrin fibers might achieve their extremely large extensibility, despite the regular arrangement of the monomeric fibrin units within a fiber. We propose that fibrin fibers accommodate large strains by two major mechanisms: (1) an alpha-helix to beta-strand conversion of the coiled coils; (2) a partial unfolding of the globular C-terminal domain of the gamma-chain.

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Natively unfolded regions of the vertebrate fibrinogen molecule

Abstract: Although it has long been realized that a large portion of the fibrinogen alpha chain has little if any defined structure, the physiological significance of this flexible appendage remains mysterious.

Cited by 37 publications

References 69 publications

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

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

Effect of Plasmin Treatment on the Fibrin Gel Formation

A Comparison of the Mechanical and Structural Properties of Fibrin Fibers with Other Protein Fibers

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