PROSITE documentation PDOC00988

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].

  +------------------------------------------------------------------------+
  |                                                               +-+      |
  |                                                               | |      |
  CxPLGxxQITASxxxxxRLxxxWxxxxWxxxxxxQGxxxxxxxxxxxxGNxxxxxxxxxxRxPxcxcLRxExGC
                        **************                          ************

 '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].