PROSITE documentation PDOC00988 [for PROSITE entry PS50022]

Coagulation factors 5/8 type C domain (FA58C) signatures and profile


Blood coagulation factors V and VIII contain a C-terminal, twice repeated, domain of about 150 amino acids, which is called F5/8 type C, FA58C, or C1/C2-like domain. A distant sequence similarity has been noted between the C1 /C2 domains of Factors V and VIII and the discoidin proteins, which comprise a family of phospholipid-binding lectins and other proteins involved in adhesive interactions [1].

In coagulation factors V and VIII the repeated domains compose part of a larger functional domain which promotes binding to anionic phospholipids on the surface of platelets and endothelial cells [2]. The C-terminal domain of the second FA58C repeat (C2) of coagulation factor VIII has been shown to be responsible for phosphatidylserine-binding and essential for activity [3,4].

The crystal structure of the FA58C domain has been solved [5] (see <PDB:1CZS>). It exhibits a distorted jelly-roll β-barrel motif, consisting of eight antiparallel strands arranged in two β-sheets. The lower part of the β-barrel is characterized by a preponderance of basic residues and three adjacent protruding loops that play a key role in lipid binding. The galactose binding domain of fungal galactose oxidase exhibits structural similarity to FA58C. The three adjacent loops are conserved and localized in a region which has been predicted to anchor the enzyme to plant cell walls. This may indicate a common binding role for the loop region.

Similar domains have been detected in other extracellular and membrane proteins [6,7,8] which are listed below:

  • Mammalian milk fat globule-EGF factor 8 (MFGM), which is expressed in milk and sperm. It is probably involved in phospholipid-binding. It contains 2 EGF-like repeats followed by 2 copies of FA58C.
  • Neuropilin (A5 antigen), a calcium-independent cell adhesion molecule that function during the formation of certain neuronal circuits. The sequence contains 2 CUB domains (see <PDOC00908>, 2 FA58C domains and a MAM domain (see <PDOC00604>).
  • Silk moth hemocytin, an humoral lectin which is involved in a self-defence mechanism. It is composed of 2 FA58C domains, a C-type lectin domain (see <PDOC00537>), 2 VWFC domains (see <PDOC00928>) and a CTCK (see <PDOC00912>).
  • Human AEBP1, a transcriptional repressor with carboxypeptidase activity that is probably involved in the regulation of the differentiation of osteoblasts. AEBP1 contains a single copy of FA58C. Mouse AEBP1 is shorter in its N-terminal and lacks part of the FA58C domain.
  • Bovine Sco-spondin, which is secreted by the subcommissural organ in embryos and is involved in the modulation of neuronal aggregation. It contains at least 2 EGF-like domains, one FA58C, and 3 LDLRA domains.
  • Drosophila neurexin IV which is required for septate junction and blood- nerve barrier formation and function. In comparision to neurexins I-α and III-α, which are composed of 6 LamG domains and 3 EGF-like repeats, the N-terminal LamG has been substituted by a FA58C domain in neurexin IV.
  • Mammalian contactin associated proteins (CASPR), which are implicated in protein-protein interactions.
  • Mammalian tyrosine-protein kinase receptors EDDR1 (CAK, DDR1, TRKE, etc) and NTRK3 (TKT or TYRO10) which all contain one copy of the FA58C domain.
  • Caenorhabditis elegans putative tyrosine-protein kinases G01D9.2, F11D5.3 and C25F6.4.

FA58C contains two conserved cysteines in most proteins, which link the extremities of the domain by a disulfide bond [9,10,11]. A further disulfide bond is located near the C-terminal of the second FA58C domain in MFGM [11].

  |                                                               +-+      |
  |                                                               | |      |
                        **************                          ************
 'C': conserved cysteine involved in a disulfide bond.
 'c': cysteine involved in a disulfide bond in MFGM.
 'x': any amino acid.
 '*': position of the patterns.
 Upper case letters: conserved residues.

We have developed two patterns for FA58C. The first is located in the middle of the domain and the second covers the C-terminal extremity. We also developed a profile that spans the whole domain. The profile also recognizes fungal galactose oxidase and some bacterial hyaluronidase and sialidase, three protein families that contain a conserved region related to the FA58C domain [1].

Last update:

December 2004 / Pattern and text revised.

Technical section

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

FA58C_3, PS50022; Coagulation factors 5/8 type C domain (FA58C) profile  (MATRIX)

FA58C_1, PS01285; Coagulation factors 5/8 type C domain (FA58C) signature 1  (PATTERN)

FA58C_2, PS01286; Coagulation factors 5/8 type C domain (FA58C) signature 2  (PATTERN)


1AuthorsBaumgartner S., Hofmann K., Chiquet-Ehrismann R., Bucher P.
TitleThe discoidin domain family revisited: new members from prokaryotes and a homology-based fold prediction.
SourceProtein Sci. 7:1626-1631(1998).
PubMed ID9684896

2AuthorsKane W.H., Davie E.W.
TitleBlood coagulation factors V and VIII: structural and functional similarities and their relationship to hemorrhagic and thrombotic disorders.
SourceBlood 71:539-555(1988).
PubMed ID3125864

3AuthorsFoster P.A., Fulcher C.A., Houghten R.A., Zimmerman T.S.
TitleSynthetic factor VIII peptides with amino acid sequences contained within the C2 domain of factor VIII inhibit factor VIII binding to phosphatidylserine.
SourceBlood 75:1999-2004(1990).
PubMed ID2110840

4AuthorsOrtel T.L., Quinn-Allen M.A., Keller F.G., Peterson J.A., Larocca D., Kane W.H.
TitleLocalization of functionally important epitopes within the second C-type domain of coagulation factor V using recombinant chimeras.
SourceJ. Biol. Chem. 269:15898-15905(1994).
PubMed ID7515064

5AuthorsMacedo-Ribeiro S., Bode W., Huber R., Quinn-Allen M.A., Kim S.W., Ortel T.L., Bourenkov G.P., Bartunik H.D., Stubbs M.T., Kane W.H., Fuentes-Prior P.
SourceNature 402:434-439(1999).

6AuthorsKane W.H., Davie E.W.
TitleCloning of a cDNA coding for human factor V, a blood coagulation factor homologous to factor VIII and ceruloplasmin.
SourceProc. Natl. Acad. Sci. U.S.A. 83:6800-6804(1986).
PubMed ID3092220

7AuthorsJohnson J.D., Edman J.C., Rutter W.J.
TitleA receptor tyrosine kinase found in breast carcinoma cells has an extracellular discoidin I-like domain.
SourceProc. Natl. Acad. Sci. U.S.A. 90:5677-5681(1993).
PubMed ID8390675

8AuthorsCouto J.R., Taylor M.R., Godwin S.G., Ceriani R.L., Peterson J.A.
TitleCloning and sequence analysis of human breast epithelial antigen BA46 reveals an RGD cell adhesion sequence presented on an epidermal growth factor-like domain.
SourceDNA Cell Biol. 15:281-286(1996).
PubMed ID8639264

9AuthorsXue J., Kalafatis M., Mann K.G.
TitleDetermination of the disulfide bridges in factor Va light chain.
SourceBiochemistry 32:5917-5923(1993).
PubMed ID8504111

10AuthorsMcMullen B.A., Fujikawa K., Davie E.W., Hedner U., Ezbahn E.
SourceProtein Sci. 4:740-746(1995).

11AuthorsHvarregaard J., Andersen M.H., Berglund L., Rasmussen J.T., Petersen T.E.
SourceEur. J. Biochem. 240:628-636(1996).

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