PROSITE documentation PDOC00445

Fibrinogen C-terminal domain signature and profile

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.