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
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References
1
Authors
Baumgartner S., Hofmann K., Chiquet-Ehrismann R., Bucher P.
Title
The discoidin domain family revisited: new members from prokaryotes and a homology-based fold prediction.
Foster P.A., Fulcher C.A., Houghten R.A., Zimmerman T.S.
Title
Synthetic factor VIII peptides with amino acid sequences contained within the C2 domain of factor VIII inhibit factor VIII binding to phosphatidylserine.
Couto J.R., Taylor M.R., Godwin S.G., Ceriani R.L., Peterson J.A.
Title
Cloning and sequence analysis of human breast epithelial antigen BA46 reveals an RGD cell adhesion sequence presented on an epidermal growth factor-like domain.
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