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Fibrinogen Synthesis, Assembly, Secretion and Regulation

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Macromolecules".

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 18629

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Special Issue Editor

Dr. Nobuo Okumura

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Guest Editor

Laboratory of Clinical Chemistry and Immunology, Department of Biomedical Laboratory Sciences, School of Health Sciences, Shinshu University
Interests: fibrinogen synthesis; fibrinogen secretion; fibrinogen assembly; afibrinogenemia; hypofibrinogenemia; fibrinogen storage disease; chaperones.

Special Issue Information

Dear Colleagues,

Plasma fibrinogen is synthesized in hepatocytes and assembled from three different polypeptide chains (Aα, Bβ, and γ) into a hexameric dimer with 29 inter- and intrachain disulfide bonds. The intracellular assembly of fibrinogen occurs in a stepwise manner with single-chain, dual-chain, and triple-chain complexes in the endoplasmic reticulum along with other post-translational modifications. However, the mechanisms of fibrinogen synthesis, assembly, and secretion and their regulation remain to be clarified. Congenital type I fibrinogen deficiencies (afibrinogenemia as a homozygote and hypofibrinogenemia as a heterozygote) are caused by genetic abnormalities and have been identified in all three genes (FGA, FGB, and FGG) as missense, nonsense, or frameshift mutations; splice-site abnormalities; or large deletions. The mechanisms of deficiency due to single-amino-acid substitutions are especially interesting. Contributions to this Special Issue will provide new insights into the mechanisms and regulation of fibrinogen biosynthesis and deepen our understanding of their biological role in health and disease.

Dr. Nobuo Okumura
Guest Editor

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Keywords

fibrinogen synthesis
fibrinogen secretion
fibrinogen assembly
afibrinogenemia
hypofibrinogenemia
fibrinogen storage disease
chaperones

Published Papers (6 papers)

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Research

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18 pages, 2521 KiB

Open AccessArticle

Development of Transient Recombinant Expression and Affinity Chromatography Systems for Human Fibrinogen

by Grega Popovic, Nicholas C. Kirby, Taylor C. Dement, Kristine M. Peterson, Caroline E. Daub, Heather A. Belcher, Martin Guthold, Adam R. Offenbacher and Nathan E. Hudson

Int. J. Mol. Sci. 2022, 23(3), 1054; https://doi.org/10.3390/ijms23031054 - 19 Jan 2022

Cited by 6 | Viewed by 3279

Abstract

Fibrin forms the structural scaffold of blood clots and has great potential for biomaterial applications. Creating recombinant expression systems of fibrinogen, fibrin’s soluble precursor, would advance the ability to construct mutational libraries that would enable structure–function studies of fibrinogen and expand the utility of fibrin as a biomaterial. Despite these needs, recombinant fibrinogen expression systems, thus far, have relied on the time-consuming creation of stable cell lines. Here we present tests of a transient fibrinogen expression system that can rapidly generate yields of 8–12 mg/L using suspension HEK Expi293^TM cells. We report results from two different plasmid systems encoding the fibrinogen cDNAs and two different transfection reagents. In addition, we describe a novel, affinity-based approach to purifying fibrinogen from complex media such as human plasma. We show that using a high-affinity peptide which mimics fibrin’s knob ‘A’ sequence enables the purification of 50–75% of fibrinogen present in plasma. Having robust expression and purification systems of fibrinogen will enable future studies of basic fibrin(ogen) biology, while paving the way for the ubiquitous use of fibrin as a biomaterial. Full article

(This article belongs to the Special Issue Fibrinogen Synthesis, Assembly, Secretion and Regulation)

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17 pages, 4245 KiB

Open AccessArticle

Structural and Functional Characterization of Four Novel Fibrinogen Mutations in FGB Causing Congenital Fibrinogen Disorder

by Eliška Ceznerová, Jiřina Kaufmanová, Žofie Sovová, Jana Štikarová, Jan Loužil, Roman Kotlín and Jiří Suttnar

Int. J. Mol. Sci. 2022, 23(2), 721; https://doi.org/10.3390/ijms23020721 - 10 Jan 2022

Cited by 3 | Viewed by 1681

Abstract

Congenital fibrinogen disorders are caused by mutations in genes coding for fibrinogen and may lead to various clinical phenotypes. Here, we present a functional and structural analysis of 4 novel variants located in the FGB gene coding for fibrinogen Bβ chain-heterozygous missense BβY416C and BβA68S, homozygous nonsense BβY345*, and heterozygous nonsense BβW403* mutations. The cases were identified by coagulation screening tests and further investigated by various methods. Fibrin polymerization had abnormal development with decreased maximal absorbance in all patients. Plasmin-induced fibrin degradation revealed different lytic phases of BβY416C and BβW403* than those of the control. Fibrinopeptide cleavage measured by reverse phase high pressure liquid chromatography of BβA68S showed impaired release of fibrinopeptide B. Morphological properties, studied through scanning electron microscopy, differed significantly in the fiber thickness of BβY416C, BβA68S, and BβW403*, and in the fiber density of BβY416C and BβW403*. Finally, homology modeling of BβA68S showed that mutation caused negligible alternations in the protein structure. In conclusion, all mutations altered the correct fibrinogen function or structure that led to congenital fibrinogen disorders. Full article

(This article belongs to the Special Issue Fibrinogen Synthesis, Assembly, Secretion and Regulation)

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14 pages, 3890 KiB

Open AccessArticle

Recombinant γY278H Fibrinogen Showed Normal Secretion from CHO Cells, but a Corresponding Heterozygous Patient Showed Hypofibrinogenemia

by Tomu Kamijo, Takahiro Kaido, Masahiro Yoda, Shinpei Arai, Kazuyoshi Yamauchi and Nobuo Okumura

Int. J. Mol. Sci. 2021, 22(10), 5218; https://doi.org/10.3390/ijms22105218 - 14 May 2021

Cited by 1 | Viewed by 2388

Abstract

We identified a novel heterozygous hypofibrinogenemia, γY278H (Hiroshima). To demonstrate the cause of reduced plasma fibrinogen levels (functional level: 1.12 g/L and antigenic level: 1.16 g/L), we established γY278H fibrinogen-producing Chinese hamster ovary (CHO) cells. An enzyme-linked immunosorbent assay demonstrated that synthesis of γY278H fibrinogen inside CHO cells and secretion into the culture media were not reduced. Then, we established an additional five variant fibrinogen-producing CHO cell lines (γL276P, γT277P, γT277R, γA279D, and γY280C) and conducted further investigations. We have already established 33 γ-module variant fibrinogen-producing CHO cell lines, including 6 cell lines in this study, but only the γY278H and γT277R cell lines showed disagreement, namely, recombinant fibrinogen production was not reduced but the patients’ plasma fibrinogen level was reduced. Finally, we performed fibrinogen degradation assays and demonstrated that the γY278H and γT277R fibrinogens were easily cleaved by plasmin whereas their polymerization in the presence of Ca²⁺ and “D:D” interaction was normal. In conclusion, our investigation suggested that patient γY278H showed hypofibrinogenemia because γY278H fibrinogen was secreted normally from the patient’s hepatocytes but then underwent accelerated degradation by plasmin in the circulation. Full article

(This article belongs to the Special Issue Fibrinogen Synthesis, Assembly, Secretion and Regulation)

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Review

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17 pages, 1854 KiB

Open AccessReview

Extension of the Human Fibrinogen Database with Detailed Clinical Information—The αC-Connector Segment

by Zofie Sovova, Klara Pecankova, Pavel Majek and Jiri Suttnar

Int. J. Mol. Sci. 2022, 23(1), 132; https://doi.org/10.3390/ijms23010132 - 23 Dec 2021

Cited by 2 | Viewed by 2500

Abstract

Fibrinogen, an abundant plasma glycoprotein, is involved in the final stage of blood coagulation. Decreased fibrinogen levels, which may be caused by mutations, are manifested mainly in bleeding and thrombotic disorders. Clinically relevant mutations of fibrinogen are listed in the Human Fibrinogen Database. For the αC-connector (amino acids Aα240–410, nascent chain numbering), we have extended this database, with detailed descriptions of the clinical manifestations among members of reported families. This includes the specification of bleeding and thrombotic events and results of coagulation assays. Where available, the impact of a mutation on clotting and fibrinolysis is reported. The collected data show that the Human Fibrinogen Database reports considerably fewer missense and synonymous mutations than the general COSMIC and dbSNP databases. Homozygous nonsense or frameshift mutations in the αC-connector are responsible for most clinically relevant symptoms, while heterozygous mutations are often asymptomatic. Symptomatic subjects suffer from bleeding and, less frequently, from thrombotic events. Miscarriages within the first trimester and prolonged wound healing were reported in a few subjects. All mutations inducing thrombotic phenotypes are located at the identical positions within the consensus sequence of the tandem repeats. Full article

(This article belongs to the Special Issue Fibrinogen Synthesis, Assembly, Secretion and Regulation)

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18 pages, 1036 KiB

Open AccessReview

Fibrinogen and Antifibrinolytic Proteins: Interactions and Future Therapeutics

by Nikoletta Pechlivani, Katherine J. Kearney and Ramzi A. Ajjan

Int. J. Mol. Sci. 2021, 22(22), 12537; https://doi.org/10.3390/ijms222212537 - 21 Nov 2021

Cited by 6 | Viewed by 4079

Abstract

Thrombus formation remains a major cause of morbidity and mortality worldwide. Current antiplatelet and anticoagulant therapies have been effective at reducing vascular events, but at the expense of increased bleeding risk. Targeting proteins that interact with fibrinogen and which are involved in hypofibrinolysis represents a more specific approach for the development of effective and safe therapeutic agents. The antifibrinolytic proteins alpha-2 antiplasmin (α2AP), thrombin activatable fibrinolysis inhibitor (TAFI), complement C3 and plasminogen activator inhibitor-2 (PAI-2), can be incorporated into the fibrin clot by FXIIIa and affect fibrinolysis by different mechanisms. Therefore, these antifibrinolytic proteins are attractive targets for the development of novel therapeutics, both for the modulation of thrombosis risk, but also for potentially improving clot instability in bleeding disorders. This review summarises the main properties of fibrinogen-bound antifibrinolytic proteins, their effect on clot lysis and association with thrombotic or bleeding conditions. The role of these proteins in therapeutic strategies targeting the fibrinolytic system for thrombotic diseases or bleeding disorders is also discussed. Full article

(This article belongs to the Special Issue Fibrinogen Synthesis, Assembly, Secretion and Regulation)

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20 pages, 2054 KiB

Open AccessReview

Fibrin(ogen) as a Therapeutic Target: Opportunities and Challenges

by Thembaninkosi G. Gaule and Ramzi A. Ajjan

Int. J. Mol. Sci. 2021, 22(13), 6916; https://doi.org/10.3390/ijms22136916 - 28 Jun 2021

Cited by 12 | Viewed by 3498

Abstract

Fibrinogen is one of the key molecular players in haemostasis. Thrombin-mediated release of fibrinopeptides from fibrinogen converts this soluble protein into a network of fibrin fibres that form a building block for blood clots. Thrombin-activated factor XIII further crosslinks the fibrin fibres and incorporates antifibrinolytic proteins into the network, thus stabilising the clot. The conversion of fibrinogen to fibrin also exposes binding sites for fibrinolytic proteins to limit clot formation and avoid unwanted extension of the fibrin fibres. Altered clot structure and/or incorporation of antifibrinolytic proteins into fibrin networks disturbs the delicate equilibrium between clot formation and lysis, resulting in either unstable clots (predisposing to bleeding events) or persistent clots that are resistant to lysis (increasing risk of thrombosis). In this review, we discuss the factors responsible for alterations in fibrin(ogen) that can modulate clot stability, in turn predisposing to abnormal haemostasis. We also explore the mechanistic pathways that may allow the use of fibrinogen as a potential therapeutic target to treat vascular thrombosis or bleeding disorders. Better understanding of fibrinogen function will help to devise future effective and safe therapies to modulate thrombosis and bleeding risk, while maintaining the fine balance between clot formation and lysis. Full article

(This article belongs to the Special Issue Fibrinogen Synthesis, Assembly, Secretion and Regulation)

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