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
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 . 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  (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
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
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
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 .
'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
December 2004 / Pattern and text revised.
PROSITE methods (with tools and information) covered by this documentation:
Baumgartner S., Hofmann K., Chiquet-Ehrismann R., Bucher P.
The discoidin domain family revisited: new members from prokaryotes and a homology-based fold prediction.
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