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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.

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.

Doolittle R.F.

September 2008 / Text revised; profile added.

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

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

Sequences known to belong to this class detected by the profile: ALL Other sequence(s) detected in Swiss-Prot: NONE.

• Domain architecture view of Swiss-Prot proteins matching PS51406 • Retrieve an alignment of Swiss-Prot true positive hits:   Clustal format, color, condensed view  / Clustal format, color  / Clustal format, plain text  / Fasta format • Retrieve the sequence logo from the alignment • Taxonomic tree view of all Swiss-Prot/TrEMBL entries matching PS51406 • Retrieve a list of all Swiss-Prot/TrEMBL entries matching PS51406 • Scan Swiss-Prot/TrEMBL entries against PS51406 • view ligand binding statistics

Matching PDB structures: 1DEQ 1EI3 1FIB 1FIC ... [ALL]

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

Consensus pattern: W-W-[LIVMFYW]-x(2)-C-x(2)-[GSA]-x(2)-N-G C is involved in a disulfide bond Sequences known to belong to this class detected by the pattern: ALL Other sequence(s) detected in Swiss-Prot: NONE.

• Retrieve an alignment of Swiss-Prot true positive hits:   Clustal format, color, condensed view  / Clustal format, color  / Clustal format, plain text  / Fasta format • Retrieve the sequence logo from the alignment • Taxonomic tree view of all Swiss-Prot/TrEMBL entries matching PS00514 • Retrieve a list of all Swiss-Prot/TrEMBL entries matching PS00514 • Scan Swiss-Prot/TrEMBL entries against PS00514 • view ligand binding statistics

Matching PDB structures: 1DEQ 1EI3 1FIB 1FIC ... [ALL]

1	Authors	Doolittle R.F.
	Title	Fibrinogen and fibrin.
	Source	Annu. Rev. Biochem. 53:195-229(1984).
	PubMed ID	6383194
	DOI	10.1146/annurev.bi.53.070184.001211

2	Authors	Spraggon G., Everse S.J., Doolittle R.F.
	Title	Crystal structures of fragment D from human fibrinogen and its crosslinked counterpart from fibrin.
	Source	Nature 389:455-462(1997).
	PubMed ID	9333233
	DOI	10.1038/38947

3	Authors	Xu X., Doolittle R.F.
	Title	Presence of a vertebrate fibrinogen-like sequence in an echinoderm.
	Source	Proc. Natl. Acad. Sci. U.S.A. 87:2097-2101(1990).
	PubMed ID	2315305

4	Authors	Baker N.E., Mlodzik M., Rubin G.M.
	Title	Spacing differentiation in the developing Drosophila eye: a fibrinogen-related lateral inhibitor encoded by scabrous.
	Source	Science 250:1370-1377(1990).
	PubMed ID	2175046

5	Authors	Kairies N., Beisel H.G., Fuentes-Prior P., Tsuda R., Muta T., Iwanaga S., Bode W., Huber R., Kawabata S.
	Title	The 2.0-A crystal structure of tachylectin 5A provides evidence for the common origin of the innate immunity and the blood coagulation systems.
	Source	Proc. Natl. Acad. Sci. U.S.A. 98:13519-13524(2001).
	PubMed ID	11707569
	DOI	10.1073/pnas.201523798

6	Authors	Barton W.A., Tzvetkova-Robev D., Miranda E.P., Kolev M.V., Rajashankar K.R., Himanen J.P., Nikolov D.B.
	Title	Crystal structures of the Tie2 receptor ectodomain and the angiopoietin-2-Tie2 complex.
	Source	Nat. Struct. Mol. Biol. 13:524-532(2006).
	PubMed ID	16732286
	DOI	10.1038/nsmb1101

7	Authors	Kostelansky M.S., Lounes K.C., Ping L.F., Dickerson S.K., Gorkun O.V., Lord S.T.
	Title	Calcium-binding site beta 2, adjacent to the 'b' polymerization site, modulates lateral aggregation of protofibrils during fibrin polymerization.
	Source	Biochemistry 43:2475-2483(2004).
	PubMed ID	14992585
	DOI	10.1021/bi0359978

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