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PROSITE documentation PDOC00445

Fibrinogen C-terminal domain signature and profile





Description

Fibrinogen, the principal protein of vertebrate blood clotting is a hexamer containing two sets of three different chains (α, β, and γ), linked to each other by disulfide bonds [1,2]. The N-terminal sections of these three chains contain the cysteines that participate in the cross-linking of the chains. The C-terminal parts of the α, β and γ chains contain a domain of about 225 amino-acid residues, which can function as a molecular recognition unit [2,3,4,5,6]. In fibrinogen as well as in angiopoietin this domain is implicated in protein-protein interactions. In lectins, such as mammalian ficolins and invertebrate tachylectin 5A, the fibrinogen C-terminal domain binds carbohydrates. As shown in the schematic representation this domain contains four conserved cysteines involved in two disulfide bonds.

                                                           *****
  xxxxxxCxxxxxxxxxxxxCxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxCxxxxxCxxxxxxxxxxxxx
        |            |                                 |     |
        +------------+                                 +-----+
               A                    B               P
'C': conserved cysteine involved in a disulfide bond.
'*': position of the pattern.
'A,B,P': regions within the domain

The 3D structure of the fibrinogen C-terminal domain (see <PDB:1FZA; F>) shows a fold composed of three separate regions [2,5,6,7]. The N-terminal region, also termed A domain, forms a helix and a β-sheet held together by the first disulfide bond. The second region, or B domain, is the largest. The third region, also termed P domain, forms long extended coil regions and contains the C-terminal disulfide bond. This P region is the most divergent and contains most ligand binding sites and in some cases residues implicated in calcium binding.

Some proteins known to contain a fibrinogen C-terminal domain:

  • Vertebrate fibrinogen α, β and γ chains.
  • Mammalian tenascin-X, an extracellular matrix protein that mediates interactions between cells and the extracellular matrix and accelerates collagen fibril formation. The C-terminal fibrinogen domain binds with fibrillar proteins in the extracellular matrix.
  • Vertebrate angiopoietin proteins, which contain a C-terminal fibrinogen domain that interacts with tyrosine-protein kinase receptor TIE2.
  • Mammalian prothrombinase or fibroleukin.
  • Sea cucumber fibrinogen-like protein A.
  • Fruit fly protein scabrous (gene sca). Scabrous is involved in the regulation of neurogenesis in Drosophila and may encode a lateral inhibitor of R8 cells differentiation.
  • Horseshoe crab techylectin-5A, a nonself-recognizing lectin with a fibrinogen C-terminal domain that recognizes carbohydrates.
  • Mammalian ficolins, with a collagen-like domain and a C-terminal fibrinogen domain that contains potential calcium-binding sites and can interact with GlcNAc.

As a signature pattern for this domain, we selected the region around the fourth cysteine. We also developed a profile that covers the entire fibrinogen C-terminal domain.

Note:

In contactin-associated proteins (Cntnap/Caspr) and intelectins (Itln) only the N-terminal 'A' region of the fibrinogen C-terminal domain is well conserved and detected.

Expert(s) to contact by email:

Doolittle R.F.

Last update:

September 2008 / Text revised; profile added.

Technical section

PROSITE methods (with tools and information) covered by this documentation:

FIBRINOGEN_C_2, PS51406; Fibrinogen C-terminal domain profile  (MATRIX)

FIBRINOGEN_C_1, PS00514; Fibrinogen C-terminal domain signature  (PATTERN)


References

1AuthorsDoolittle R.F.
TitleFibrinogen and fibrin.
SourceAnnu. Rev. Biochem. 53:195-229(1984).
PubMed ID6383194
DOI10.1146/annurev.bi.53.070184.001211

2AuthorsSpraggon G., Everse S.J., Doolittle R.F.
TitleCrystal structures of fragment D from human fibrinogen and its crosslinked counterpart from fibrin.
SourceNature 389:455-462(1997).
PubMed ID9333233
DOI10.1038/38947

3AuthorsXu X., Doolittle R.F.
TitlePresence of a vertebrate fibrinogen-like sequence in an echinoderm.
SourceProc. Natl. Acad. Sci. U.S.A. 87:2097-2101(1990).
PubMed ID2315305

4AuthorsBaker N.E., Mlodzik M., Rubin G.M.
TitleSpacing differentiation in the developing Drosophila eye: a fibrinogen-related lateral inhibitor encoded by scabrous.
SourceScience 250:1370-1377(1990).
PubMed ID2175046

5AuthorsKairies N., Beisel H.G., Fuentes-Prior P., Tsuda R., Muta T., Iwanaga S., Bode W., Huber R., Kawabata S.
TitleThe 2.0-A crystal structure of tachylectin 5A provides evidence for the common origin of the innate immunity and the blood coagulation systems.
SourceProc. Natl. Acad. Sci. U.S.A. 98:13519-13524(2001).
PubMed ID11707569
DOI10.1073/pnas.201523798

6AuthorsBarton W.A., Tzvetkova-Robev D., Miranda E.P., Kolev M.V., Rajashankar K.R., Himanen J.P., Nikolov D.B.
TitleCrystal structures of the Tie2 receptor ectodomain and the angiopoietin-2-Tie2 complex.
SourceNat. Struct. Mol. Biol. 13:524-532(2006).
PubMed ID16732286
DOI10.1038/nsmb1101

7AuthorsKostelansky M.S., Lounes K.C., Ping L.F., Dickerson S.K., Gorkun O.V., Lord S.T.
TitleCalcium-binding site beta 2, adjacent to the 'b' polymerization site, modulates lateral aggregation of protofibrils during fibrin polymerization.
SourceBiochemistry 43:2475-2483(2004).
PubMed ID14992585
DOI10.1021/bi0359978



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