Skip to main content
SpringerLink
Log in

Structure and function of human fibrinogen inferred from dysfibrinogens

  • Update on Hemostasis and Thrombosis
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

Fibrinogen is a 340-kDa plasma protein that is composed of two identical molecular halves, each consisting of three non-identical subunit polypeptides designated as Aa, Bβ- and λ-chains held together by multiple disulfide bonds. Fibrinogen has a trinodular structure, i.e., one central E domain comprizing the amino-terminal regions of paired individual three polypeptides, and two identical outer D domains. These three nodules are linked by two coiled-coil regions [1,2]. After activation with thrombin, a tripeptide segment consisting of Gly-Pro-Arg is exposed at the amino-terminus of each α-chain residing at the center of the E domain and combines with its complementary binding site, called the ‘a’ site, residing in the carboxyl-terminal region of the γ-chain in the outer D domain of another molecule. By crystallographic analysis [3], the α-amino group of αGly-1 is shown to be juxtaposed between the carboxyl group of γAsp-364 and the carboxyamide of Gln-329 in the ‘a’ site. Half molecule-staggered, double-stranded fibrin protofibrils are thus formed [4,5]. Upon abutment of two adjacent D domains on the same strand, D-D self association takes place involving Arg-275, Tyr-280 and Ser-300 of the γ-chain on the surface of the abutting two D domains [3]. Thereafter, carboxyl-terminal regions of the fibrin α-chains are thought to be untethered and interact with those of other protofibrils leading to the formation of thick fibrin bundles and interwoven networks after appropriate branching [6–9]. Although many enigmas still remain regarding the mechanisms of these molecular interactions, fibrin assembly proceeds in a highly ordered fashion. In my talk, I would like to discuss these molecular interactions of fibrinogen and fibrin based on the up-date data provided by analyses of normal as well as hereditary dysfibrinogens, particularly in the latter by introducing representative molecules at each step of fibrin clot formation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Doolittle RE, H. Bouma Iii, BA Cottrell, et al. The covalent structure of human fibirinogen. In the chemistry and physiology of the human plasma proteins. D.H. Bing, Ed.: Pergamon Press, New York. 1979. p77–95.

    Google Scholar 

  2. Doolittle RE. Fibirinogen and fibrin. In Haemostasis and Thrombosis, 2nd edit. A.L. Bloom & D.P. Thomas, Eds.: Churchil Livingstone, Edinburgh. 1981. p163–191.

    Google Scholar 

  3. Spraggon G, Everse S, Doolittle RE Crystal structures of fragment D from human fibrinogen and its crosslinked counterpart from fibrin.Nature. 1997;389:455–462.

    Article  PubMed  CAS  Google Scholar 

  4. Cote HCE, Pratt KP Davie EW, Chung DW. The polymerization pocket ‘a’ within the carboxyl-terminal region of the γ chain of human fibrinogen is adjacent to but independent from the calcium-binding site.J Biol Chem. 1977;272:23792–23798.

    Article  Google Scholar 

  5. Everse SJ, Spraggon G, Doolittle FE. A three dimensional consideration of varian human fibrinogens.Thromb Haemost. 1998;80:1–9.

    PubMed  CAS  Google Scholar 

  6. Weisel JW. Lateral aggregation and the role of the two pairs of fibrinopeptides.Biophys J. 1986;50:1079–1093.

    Article  PubMed  CAS  Google Scholar 

  7. Weisel JW, Veklich Y, Gorkun O. The sequence of cleavage of fibrinopeptides from fibrinogen is important for protofibril formation and enhancemenet of lateral aggregation in fibrin clots.J Mol Biol. 1993;232:285–297.

    Article  PubMed  CAS  Google Scholar 

  8. Gorkun OV, Veklich YI, Medved LV, et al. Role of the αC domains of fibrin in clot formation.Biochemistry. 1994;33: 6986–6997.

    Article  PubMed  CAS  Google Scholar 

  9. Veklich LV, Gorkun OV, Medved LV, et al. Carboxyl-terminal portions of the α chains of fibrinogen and fibrin. Localization by electron microscopy and the effects of isolated α fragments on polymerization.J Biol Chem. 1993; 268:13577–13585.

    PubMed  CAS  Google Scholar 

  10. Matsuda M, Sugo T, Yoshida N, et al. Structure and function of fibrinogen: insights fromdysfibrinogens.Thromb Haemost. 1999;82:291–297.

    Google Scholar 

  11. Matsuda M. Structure and function of fibrinogen inferred from hereditary dysfibrinogens.Fibrinolysis & Proteolysis. 2000;14:187–197.

    Article  CAS  Google Scholar 

  12. Matsuda M, Sugo T. Hereditary disorders of fibrinogen.Anal N.Y. Acad Sci. 2001;936:65–88.

    Article  CAS  Google Scholar 

  13. Mosesson MW, Diorio JP, Siebenlist KR, et al. Evidence for a second type of fibrin branch point in fibrin polymer networks, the trimolecular branch junction.Blood. 1993;82:1517–1521.

    PubMed  CAS  Google Scholar 

  14. Baradet TC, Haselgrove JC, Weisel JW. Three-dimensional reconstruction of fibrin clot networks from stereoscopic intermediate voltage electron microscopic images and analysis of branching.Biophys J. 1995;68:1551–1560.

    Article  PubMed  CAS  Google Scholar 

  15. Yee VC, Pratt KP, Cote HCF, et al. Crystal structure of a 30 kDa C-terminal fragment from the γchain of human fibrinogen.Structure. 1997;5:125–138.

    Article  PubMed  CAS  Google Scholar 

  16. Pratt KP, Cote HCF, Chung DW, et al. The fibrin polymerization pocket; three-dimension structure of a 30 kDA C-terminalγchain fragment complexed with the peptide Gly-Pro-Arg-Pro.Proc Atl Acad Sci. U.S.A. 1997;94:7176–7181.

    Article  CAS  Google Scholar 

  17. Southan C. The elucidation of molecular defects in congenital dysfibrinogenemia. In: Fibrinogen, Fibrin Stabilization, and Fibrinolysis. J.L. Francis, Ed.: 1998. p199–127.

  18. Niwa K, Yaginuma A, Nakanishi M, et al. Fbirinogen Mitaka II: a hereditary dysfibrinogen with defective thrombin binding caused by an Aα Glu-11 to Gly substitution.Blood. 1993;82:3658–2663.

    PubMed  CAS  Google Scholar 

  19. Martin PD, Robertson W, Turk D, et al. The structure of residues 7–16 of the Aα-chain of human fibrinogen bound to bovine thrombin at 2.3-Å resolution.J Biol Chem. 1992;267:7911–7920.

    PubMed  CAS  Google Scholar 

  20. Stubb MT, Aschkinant H, Mayer I, et al. The interaction of thrombin with fibirinogen. A structural basis for its specificity.Eur J Biochem. 1992;206:187–195.

    Article  Google Scholar 

  21. Zheng Z, Ashton RW, Ni F, Scheraga HA. Thrombin hydrolysis of an N-terminal peptide from fibirinogenn Lille: kinetic and NMR studies.Biochemistry. 1992;31:4426–4431.

    Article  PubMed  CAS  Google Scholar 

  22. Higgins DL, Shafer JA. Fibirinogen Petoskey, a dysfibirinogenemia characterized by replacement of Arg-Aα16 by a histidy residue. Evidence for thrombincatalyzed hydrolysis at a histidyl residue.J Biol Chem. 1981;256:12013–12017.

    PubMed  CAS  Google Scholar 

  23. Henschen A, Kehl M, Southan S. Genetically abnormal fibinogens-strategies for structure elucidation, including fibirinopeptide analysis. In: Variants of Human Fibrinogen E.A. Beck & M. Furlan. Eds.: Hans Huber Bverlag, Bern. 1984. p273–320.

    Google Scholar 

  24. Matsuda M. Molecular abnormalities of fibrinogen-the present status of structure elucidation. In: Fibirinogen 4. Current Basis and Clinical Aspects. M. Matsuda, S. Iwanaga, A. Takada & A. Henschen, Eds. Excerpta Medica, Amsterdam. 1990. p139–152.

    Google Scholar 

  25. Galanakis D. Ingerited dysfibrinogenemia: emerging abnormal structure associations with pathologic and nonpathologic dysfunctions.Semin Throm Hemostas. 1993;19:386–395.

    Article  CAS  Google Scholar 

  26. Kudryk BJ, Collen D, Woods KR, Blombck. evidence for localization of polymerization sites infibrinogen.J Biol Chem. 1974;249:3322–3325.

    PubMed  CAS  Google Scholar 

  27. Olexa SA, Budzynski AZ. Evidence for four different polymerization sites involved in human fibrin formation.Proc Natl Acad Sci USA. 1980;77:1374–1378.

    Article  PubMed  CAS  Google Scholar 

  28. Mosesson MW, Siebenlist KR, Dioliio JP, et al. The role of fibrinogen D domain intermolecular association sites in the plymerization of fibrin and fibrinogen Tokyo II (γ275 Arg→Cys).J Clin Invest. 1995;96:1053–1058.

    Article  PubMed  CAS  Google Scholar 

  29. Laudano AP, Doolittle RF. Synthetic peptide derivatives that bind to fibirinogen and prevent the plymerization of fibrin monomers.Proc Natl Acad Sci. U.S.A. 1978;75:3085–3089.

    Article  PubMed  CAS  Google Scholar 

  30. Ludano AP, Dollittle RF. Studies on synthetic peptides that bind to fibirinogen and prevent fibrin polymerization. Structural requirements, number of binding sites, and species differences.Biochemistry. 1980;19:1013–1019.

    Article  Google Scholar 

  31. Wada Y, Niwa K, Maekawa H, et al. A new type of congenital dysfibrinogen, fibrinogen Bremen, with an Aα Gly-17 to Val substitution associated with hemorrhagic diathesis and delayed wound healing.Thromb Haemost. 1993;70:397–403.

    PubMed  CAS  Google Scholar 

  32. Yoshida N, Okuma MO, Hirata H, et al. Fibrinogenn Kyoto II, a new congenitally abnormal molecule, characterized by the replacement of Aα proline-18 by leucine.Blood. 1991; 78:149–153.

    PubMed  CAS  Google Scholar 

  33. Uotani C, Miyata T, Kumabashiri I, et al. Fibrinogen Kanazawa: a congenital dysfibirinogenemia with delayed polymerization having a replacement of proline-18 by leucine in the A α-chain.Blood Coag Fibrinol. 1991;2:413–417.

    Article  CAS  Google Scholar 

  34. Blonb · Ck, M, Blonb · Ck, EF Mammen, Prasad AS. Fibiriogen Detroit-A molecular defect in the N-terminal disulphide knot of human fibrinogen?Nature. 1968;218:134–137.

    Article  Google Scholar 

  35. Hessel B, Stenbjerg S, Dyr J, et al. Fbirinogen Aarhus-a new case of dysfibrinogenemia.Thromb Res. 1986;42:21–37.

    Article  PubMed  CAS  Google Scholar 

  36. Dempfle CEH, Henschen A. Fibrinogen Mannheim I-identification of an Aα C19 Arg→Gly substitution in dysfibrinogenemia associated with bleeding tendency. In: Fibrinogen 4. Current Basic and Clinical Aspects. Matsuda M, Iwanaga S, Takada A, Henschen A, Eds. Elevier Science Publ. Amsterdam. 1990, p159–166.

    Google Scholar 

  37. Yamaguchi S, Sugo T, Hashimoto Y, et al. Fibrinogen Kumamoto with an Aα Arg-19 to Gly substituion has reduced affinity for thrombin: possible relevance to thrombosis. Jpn.J Throm Haemost. 1997;8:382–392.

    CAS  Google Scholar 

  38. Miyata T, Furukawa K, Iwanaga S, et al. Fibrinogen Nagoya, a replacement of glutamine-329 by arginine in the γ-chain that impairs the polymerization of fibirin monomer.J Biochem. 1989;105:10–14.

    PubMed  CAS  Google Scholar 

  39. Reber P, Furlan M, Rupp C, et al. Characterizatioon of fibirinogen Milano I: amino acid exchangeγ330 Asp→Val impairs fibrin polymerization.Blood. 1986;67:1751–1756.

    PubMed  CAS  Google Scholar 

  40. Terukina S, Yamazumi K, Okamoto K, et al. Fibirinogen Kyoto III: a congenital daysfibrinogen with a γ aspartic acid-330 to tyrosine substitution manifesting impaired fibrin monomer polymerization.Blood. 1989;74:2681–2687.

    PubMed  CAS  Google Scholar 

  41. Okamura N, Furihata K, Terasawa F, et al. Fibirinogen Matsumoto I: aγ 364 Asp→His. (GAT→CAT) substitution associated with defective fibrin polymerization.Thromb Haemost. 1996;75:887–891.

    Google Scholar 

  42. Bentolia S, Samama MM, Conard J, et al. Association of dysfibrinogenemia and thrombosis. Apropos of a family (fibirinogen Melun) and review of the literature (in French).Annalen Med Interne. 1995;146:575–580.

    Google Scholar 

  43. Ct HCF, Lord ST, Pratt KP. γ-chain dysfibrinogenemias: molecular structure-function relationships of naturally occurring mutations in the γ chain of human fibrinogen.Blood. 1998; 92:2195–2212.

    Google Scholar 

  44. Yoshida N, Hirata H, Morigami Y, et al. Characterization of an abnormal fibirinogen Osaka V with the replacement of γ-arginine 375 by glycine.J Biol Chem. 1992;267:2753–2759.

    PubMed  CAS  Google Scholar 

  45. Steinmann C, Rebver P, Jungo M, et al. Fibirinogen Bern I: substitutionγ337 Asn→Lys is responsible for defective fibrin monomer polymerization.Blood. 1993;82:2104–2108.

    PubMed  CAS  Google Scholar 

  46. Steinmann C, Bgli C, Jungo M, et al. A new substitution, γ 358 Ser→Cys, in fibrinogen Milano VII causes defective fibrin polymerization.Blood. 1994;84:1874–1880.

    PubMed  CAS  Google Scholar 

  47. Matsuda M, Nakamikawa C, Baba M, Morimoto K. Fibrinogen Tokyo II: an abnormal fibirinogen with an impaired polymerization site on the aligned DD domain of fibrin molecules.J Clin Invest. 1983;72:1034–1041.

    Article  PubMed  CAS  Google Scholar 

  48. Terukina S, Matsuda M, Hirata H, et al. Substitution of γ Arg-275 by Cys in an abnormal fibrinogen. Fibrinogen Osaka II. Evidence for a unique solitary systine structure at themutation site.J Biol Chem. 1988;263:13579–13587.

    PubMed  CAS  Google Scholar 

  49. Reber P, Furlan M, Henschen A, et al. Three abnormal fibirnogen variants with the same amino acid substitution (γ 275 Arg→His): fibrinogens Bergamo II, Essen and Perugia.Thromb Haemost. 1986;56:401–406.

    PubMed  CAS  Google Scholar 

  50. Yamazumi K, Terukina S, Onohara S, Matsuda M. Normal plasmic cleavge of the γchain variant of fibrinogen Saga with an Arg-275 to His substitution.Thromb Haemost. 1988; 60:476–480.

    PubMed  CAS  Google Scholar 

  51. Mimuro J, Kawata Y, Niwa K, et al. A new type of Ser substitution for γArg-275 in fibrinogen Kamogawa I characterized by impaired fibrin assembly.Thromb Haemost. 1999; 81:940–944.

    PubMed  CAS  Google Scholar 

  52. Fellowes AP, Brennan SO, Ridgway HJ, et al. Electrospray ionization mass spectrometry identification of fibrinogen Banks Peninsula (γ280 Tyr→Cys): a new variant with defective polymerization.Brit Haemost. 1998;101:24–31.

    Article  CAS  Google Scholar 

  53. NIWA K, TAKEBE M, SUGO T, et al. A γGly-268 to Glu substitution is responsible for impaired fibrin assembly in a homozygous dysfibrinogen Kurashiki I.Blood. 1996;87:4686–4694.

    PubMed  CAS  Google Scholar 

  54. Yoshida N, Terukina S, Okuma M, et al. Characterization of an apparently lower molecular weight γ-chain variant in fibrinogen Kyoto I. The replacement of γ Asn-308 by Lys which caused an accelerated cleavage of fragment DI by plasmin and the generation of a new plasmin cleavage site.J Biol Chem. 1998;263:13949–13856.

    Google Scholar 

  55. Bantia S, Bell WR, Dang CV. Polymerization defect of fibirinogen Baltimore III due to a gamma Asn-308→Ile mutation.Blood. 1990;75:1659–1663.

    PubMed  CAS  Google Scholar 

  56. Yamazumi K, Shimura K, Terukina S, et al. Aγ aspargine-308 identified in a congenital dysfibrinogenemia associated with posttraumatic bleeding, fibrinogen Asahi.J Clin Invest. 1989;83:1590–1597.

    Article  PubMed  CAS  Google Scholar 

  57. Sugo T, Nakamikawa C, Yoshida N, et al. End-linked homodimers in fibrinogen Osaka VI with a Bβ-chain extension lead to fragile clot structure.Blood. 2000;96:3779–3785.

    PubMed  CAS  Google Scholar 

  58. Townsend RR, Hilliker E, Li YT, et al. Carbohydrate structure of human fibirinogen.J Biol Chem. 1982;257:9704–9710.

    PubMed  CAS  Google Scholar 

  59. Koopman J, Haverkate F, Grimbergen J, et al. Fibrinogen Marburg: a homozygous case of dysfibrinogenemia, lacking amino acids Aα461-610(Lys 461AAA→Stop TAA).Blood. 1992;80:1972–1979.

    PubMed  CAS  Google Scholar 

  60. Sugo T, Nakamikawa C, Takebe M, et al. Factor XIIIa-cross-linking of the Marburg Fibrin: Formation of αm v n-heteromultimers and the α-chain-linked albumin v complex, and disturbed protofibril assembly resulting in acquisition of plasmin-resistance relevant to thrombophilia.Blood 1998;91: 3282–3288.

    PubMed  CAS  Google Scholar 

  61. Koopman J, Haverkate F, Grimbergen J, et al. Molecular basis for fibrinogen Dusart (Aα554 Arg→Cys) and its association with abnormal fibrin polymnerization and thrombophilia.J Clin Invest. 1993;91:1637–1643.

    Article  PubMed  CAS  Google Scholar 

  62. Wada Y, Lord ST. A correlation between thrombotic disease and a specific fibirinogen abnormality (Aα 554 Arg→Cys)in two unrelated kindred, Dusart and Chapel Hill III.Blood. 1994;84:3709–3714.

    PubMed  CAS  Google Scholar 

  63. Maekawa H, Yamazumi K, Muramatsu S, et al. An Aα Ser-434 to N-glycosylated Asn substitution in a dysfibrinogen, fibrinogen Caracas II, characterized by impaired fibrin gel formation.J Biol Chem. 1991;266:11575–11581.

    PubMed  CAS  Google Scholar 

  64. Collet JP, Woodhead JL, Soria J, et al. Fibrinogen Dusart; electron microscopy of molecules, fibers and clots, and viscoelastic properties of clots.Biophys J. 1996;70:500–510.

    Article  PubMed  CAS  Google Scholar 

  65. Mosesson MW, Sievenlist KR, Hainfeld JF, et al. The relationship between the fibrinogen D domain self-association/cross-linking site (γXL) and the fibirinogen Dusart abnormality (AαR554C-albumin). Clues to thrombophilia in the Dusart syndrome,J Clin Invest. 1996;97:2342–2350.

    Article  PubMed  CAS  Google Scholar 

  66. Woodhead JL, Nagaswami C, Matsuda M, et al. The ultrastructure of fibirinogen Caracas II molecules, fibers and clots.J Biol Chem. 1996;271:4946–4953.

    Article  PubMed  CAS  Google Scholar 

  67. Maekawa H, Yamazumi K, Muramatsu S, et al. Fibrinogen Lima: a homozygous dysfibirinogen with an Aα-arginine-141 to serine substitution associated with extra N-glycosylation at Aα-asparagine-139.J Clin Invest. 1992;90:67–76.

    Article  PubMed  CAS  Google Scholar 

  68. Ridgway HJ, Brennan SO, Loreth RM, George PM. Fbirinogen Kaiserslautern (γ380 Lys to Asn): A new glycosylated fibrinogen variant with delayed polymrization.Br J Haematol. 1997;99:562–569.

    Article  PubMed  CAS  Google Scholar 

  69. Marguerie G, Chagneil G, Suscilion M. The binding of calcium to bovine fibrinogen.Biochim Biophys Acta 1977; 490: 94–103.

    PubMed  CAS  Google Scholar 

  70. Koopman J, Haverkate F, BriËte E, Lord ST. A congenitally abnormal fibirinogen (Vissingen) with a 6-base delation in the γchain gene, causing defective calcium binding and impaired fibrin polymerization.J Biol Chem 1991;266: 13456–13461.

    PubMed  CAS  Google Scholar 

  71. Suenson E, Bjerrum P, Holm A, et al. The role of fragment X plymers in the fibrin enhancement of tissue plasminogen activator-catalyzed plasmin formation.J Biol Chem. 1990;265:2228–22237.

    Google Scholar 

  72. Lijnen HR, Soria J, Soria C, et al. Dysfibrinogenemia (Fibrinogen Dusart) associated with impaired fibrin-enhanced plasminogen activation.Thromb Haemost. 1984;51:108–109.

    PubMed  CAS  Google Scholar 

  73. Carrell N, Gabriel DA, Blatt PM, et al. Heteditary dysfibrinogenemia in a patient with thrombotic disease.Blood. 1983;62:439–447.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Cell and Molecular Medicine, Center for Molecular Medicine, Jichi Medical School, Tochigi-Ken, Japan

    Michio Matsuda & Teruko Sugo

  2. Ogata Institute for Medical and Chemical Research, Tokyo, Japan

    Michio Matsuda

Authors
  1. Michio Matsuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Teruko Sugo
    View author publications

    You can also search for this author in PubMed Google Scholar

About this article

Cite this article

Matsuda, M., Sugo, T. Structure and function of human fibrinogen inferred from dysfibrinogens. Int J Hematol 76 (Suppl 1), 352–360 (2002). https://doi.org/10.1007/BF03165284

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03165284

Keywords

Search

Navigation