FA58C

Coagulation factor 5/8 C-terminal domain, discoidin domain

• SMART accession number: SM00231
• Description: Cell surface-attached carbohydrate-binding domain, present in eukaryotes and assumed to have horizontally transferred to eubacterial genomes.
• Interpro abstract (IPR000421): 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. In the Dictyostelium discoideum (Slime mold) cell adhesion protein discoidin, a related domain, named discoidin I-like domain, DLD, or DS, has been found which shares a common C-terminal region of about 110 amino acids with the FA58C domain, but whose N-terminal 40 amino acids are much less conserved. Similar domains have been detected in other extracellular and membrane proteins (PUBMED:3092220), (PUBMED:8390675), (PUBMED:8639264) 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 (PUBMED:3125864). 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 (PUBMED:2110840), (PUBMED:7515064). It forms an amphipathic alpha-helix, which binds to the membrane (PUBMED:7893714). FA58C contains two conserved cysteines in most proteins, which link the extremities of the domain by a disulphide bond (PUBMED:8504111), (PUBMED:7613471), (PUBMED:8856064). A further disulphide bond is located near the C-terminal of the second FA58C domain in MFGM Q08431 (PUBMED:8856064).

    +------------------------------------------------------------------------+
    |                                                               +-+      |
    |                                                               | |      |
    CxPLGxxQITASxxxxxRLxxxWxxxxWxxxxxxQGxxxxxxxxxxxxGNxxxxxxxxxxRxPxcxcLRxExGC
  
  'C': conserved cysteine involved in a disulphide bond.
  'c': cysteine involved in a disulphide bond in MFGM .
  'x': any amino acid.
  upper case letters: conserved residues.
  

• GO process: cell adhesion (GO:0007155)

There are 1148 FA58C domains in 858 proteins in SMART's nrdb database.

Literature (relevant references for this domain)

Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

• Baumgartner S, Hofmann K, Chiquet-Ehrismann R, Bucher P
• The discoidin domain family revisited: new members from prokaryotes and a homology-based fold prediction.
• Protein Sci. 1998; 7: 1626-31

Members of the discoidin (DS) domain family, which includes the C1 and C2 repeats of blood coagulation factors V and VIII, occur in a great variety of eukaryotic proteins, most of which have been implicated in cell-adhesion or developmental processes. So far, no three-dimensional structure of a known example of this extracellular module has been determined, limiting the usefulness of identifying a new sequence as member of this family. Here, we present results of a recent search of the protein sequence database for new DS domains using generalized profiles, a sensitive multiple alignment-based search technique. Several previously unrecognized DS domains could be identified by this method, including the first examples from prokaryotic species. More importantly, we present statistical, structural, and functional evidence that the D1 domain of galactose oxidase whose three-dimensional structure has been determined at 1.7 A resolution, is a distant member of this family. Taken together, these findings significantly expand the concept of the DS domain, by extending its taxonomic range and by implying a fold prediction for all its members. The proposed alignment with the galactose oxidase sequence makes it possible to construct homology-based three-dimensional models for the most interesting examples, as illustrated by an accompanying paper on the C1 and C2 domains of factor V.

• Saenko EL, Shima M, Rajalakshmi KJ, Scandella D
• A role for the C2 domain of factor VIII in binding to von Willebrand factor.
• J Biol Chem. 1994; 269: 11601-5

We examined the possibility that the C2 domain, amino acid residues 2173-2332, of factor VIII (fVIII) contains a binding site for von Willebrand factor (vWf) to clarify previous data showing that some monoclonal and human inhibitor antibodies with epitopes in C2 prevent fVIII-vWf binding. We constructed a fusion protein, glutathione S-transferase-C2, which binds to immobilized vWf in a dose-dependent saturable fashion, suggesting that the fVIII C2 domain contains a binding site for vWf. This site was further localized by testing the effect of a synthetic peptide on fVIII-vWf binding. Peptide 2303-2332, consisting of a previously identified phosphatidyl-serine binding site, prevented fVIII binding to vWf, suggesting that the sites for fVIII binding to vWf or phosphatidylserine have some overlap. The effect of anti-C2 domain antibodies further supported these observations. The inhibition of fVIII binding to vWf by monoclonal antibody NMC-VIII/5 IgG or F(ab)'2 (epitope within residues 2170-2327) and by inhibitor antibody MU IgG or Fab' (epitope within residues 2248-2312) was demonstrated by a fluid-phase binding assay and enzyme-linked immunosorbent assay. Two monoclonal antibodies with epitopes within amino acid residues 2170-2218 or 2248-2285, which do not overlap the phosphatidylserine binding site, did not have any inhibitory effect. Our data suggest that the previously described antagonistic binding of vWf and phospholipid to fVIII is due to the involvement of some C2 domain amino acids in both processes.

• Foster PA, Fulcher CA, Houghten RA, Zimmerman TS
• Synthetic factor VIII peptides with amino acid sequences contained within the C2 domain of factor VIII inhibit factor VIII binding to phosphatidylserine.
• Blood. 1990; 75: 1999-2004

The effective activation of factor X by factor IXa requires the co-factor activity of activated factor VIII (FVIII). Factor Xa formation is also dependent on the presence of negatively charged phospholipid. A phospholipid binding domain of FVIII has been reported to be present on the FVIII light chain. Recent observations on a subset of human FVIII inhibitors have implicated the carboxyl-terminal C2 domain of FVIII as containing a possible phospholipid binding site. The purpose of this study was to investigate directly the role of the C2 domain in phospholipid binding. Twenty-six overlapping peptides, which span the entire C2 domain of FVIII, were synthesized. The ability of these peptides to inhibit the binding of purified human FVIII to immobilized phosphatidylserine was evaluated in an enzyme-linked immunosorbent assay. Three overlapping synthetic FVIII peptides, 2303-2317, 2305-2332, and 2308-2322, inhibited FVIII binding to phosphatidylserine by greater than 90% when tested at a concentration of 100 mumols/L. A fourth partially overlapping peptide, 2318-2332, inhibited FVIII binding by 65%. These results suggest that the area described by these peptides, residues 2303 to 2332, may play an important role in the mediation of FVIII binding to phospholipid.

• Jenny RJ et al.
• Complete cDNA and derived amino acid sequence of human factor V.
• Proc Natl Acad Sci U S A. 1987; 84: 4846-50

cDNA clones encoding human factor V have been isolated from an oligo(dT)-primed human fetal liver cDNA library prepared with vector Charon 21A. The cDNA sequence of factor V from three overlapping clones includes a 6672-base-pair (bp) coding region, a 90-bp 5' untranslated region, and a 163-bp 3' untranslated region within which is a poly(A) tail. The deduced amino acid sequence consists of 2224 amino acids inclusive of a 28-amino acid leader peptide. Direct comparison with human factor VIII reveals considerable homology between proteins in amino acid sequence and domain structure: a triplicated A domain and duplicated C domain show approximately equal to 40% identity with the corresponding domains in factor VIII. As in factor VIII, the A domains of factor V share approximately 40% amino acid-sequence homology with the three highly conserved domains in ceruloplasmin. The B domain of factor V contains 35 tandem and approximately 9 additional semiconserved repeats of nine amino acids of the form Asp-Leu-Ser-Gln-Thr-Thr/Asn-Leu-Ser-Pro and 2 additional semiconserved repeats of 17 amino acids. Factor V contains 37 potential N-linked glycosylation sites, 25 of which are in the B domain, and a total of 19 cysteine residues.

• Kane WH, Davie EW
• Cloning of a cDNA coding for human factor V, a blood coagulation factor homologous to factor VIII and ceruloplasmin.
• Proc Natl Acad Sci U S A. 1986; 83: 6800-4

Coagulation factor V is a high molecular weight plasma glycoprotein that participates as a cofactor in the conversion of prothrombin to thrombin by factor Xa. A phage lambda gt11 Hep G2 cell cDNA expression library was screened by using an affinity-purified antibody to human factor V, and 11 positive clones were isolated and plaque-purified. The clone containing the largest cDNA insert contained 2970 nucleotides and coded for 938 amino acids, a stop codon, and 155 nucleotides of 3' noncoding sequence including a poly(A) tail. The coding region includes 651 amino acids from the carboxyl terminus that constitute the light chain of human factor Va and 287 amino acids that are part of the connecting region of the protein. The predicted amino acid sequence agreed completely with 147 amino acid residues that were identified by Edman degradation of cyanogen bromide peptides isolated from the light chain. During the activation of factor V, several peptide bonds are cleaved by thrombin, giving rise to a heavy chain, a connecting fragment(s), and a light chain. The light chain is generated by the cleavage of an Arg-Ser peptide bond. The amino acid sequence of the light chain is homologous (40%) with the carboxyl-terminal fragment (Mr, 73,000) of human factor VIII. Both fragments have a similar domain structure that includes a single ceruloplasmin-related domain followed by two C domains. The carboxyl terminus of the connecting region, however, shows no significant amino acid sequence homology with factor VIII. It is very acidic and contains a number of potential N-linked glycosylation sites. It also contains about 20 tandem repeats of nine amino acids.

• Wood WI et al.
• Expression of active human factor VIII from recombinant DNA clones.
• Nature. 1984; 312: 330-7

DNA clones encoding the complete 2,351 amino acid sequence for human factor VIII have been isolated and used to produce biologically active factor VIII in cultured mammalian cells. The recombinant protein corrects the clotting time of plasma from haemophiliacs and has many of the biochemical and immunological characteristics of serum-derived factor VIII.

Disease (disease genes where sequence variants are found in this domain)

SwissProt sequences and OMIM curated human diseases associated with missense mutations within the FA58C domain.

Protein	Disease
Retinoschisin precursor (SRS)(SMART)	OMIM:312700: Retinoschisis
Coagulation factor VIII precursor (Procoagulant component) (Antihemophilic factor) (AHF) [Contains: Factor VIIIa heavy chain, 200 kDa isoform; Factor VIIIa heavy chain, 92 kDa isoform; Factor VIII B chain; Factor VIIIa light chain] (SRS)(SMART)	OMIM:306700: Hemophilia A

Metabolism (metabolic pathways involving proteins which contain this domain)

% proteins involved	KEGG pathway ID	Description
16.67	map04360	Axon guidance
15.00	map04610	Complement and coagulation cascades
15.00	map04514	Cell adhesion molecules (CAMs)
10.00	map01032	Glycan structures - degradation
8.33	map00531	Glycosaminoglycan degradation
6.67	map00511	N-Glycan degradation
5.00	map00604	Glycosphingolipid biosynthesis - ganglioseries
5.00	map00600	Sphingolipid metabolism
5.00	map00561	Glycerolipid metabolism
5.00	map00052	Galactose metabolism
1.67	map00562	Inositol phosphate metabolism
1.67	map04512	ECM-receptor interaction
1.67	map04140	Regulation of autophagy
1.67	map04070	Phosphatidylinositol signaling system
1.67	map04510	Focal adhesion

This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with FA58C domain which could be assigned to a KEGG orthologous group, and not all proteins containing FA58C domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

Structure (3D structures containing this domain)

3D Structures of FA58C domains in PDB

PDB code	Title
1czs	Crystal structure of the c2 domain of human coagulation factor v: complex with phenylmercury
1czt	Crystal structure of the c2 domain of human coagulation factor v
1czv	Crystal structure of the c2 domain of human coagulation factor v: dimeric crystal form
1d7p	Crystal structure of the c2 domain of human factor viii at 1.5 a resolution at 1.5 a
1eut	Sialidase, large 68kd form, complexed with galactose
1euu	Sialidase or neuraminidase, large 68kd form
1gof	Novel thioether bond revealed by a 1.7 angstroms crystal structure of galactose oxidase
1gog	Novel thioether bond revealed by a 1.7 angstroms crystal structure of galactose oxidase
1goh	Novel thioether bond revealed by a 1.7 angstroms crystal structure of galactose oxidase
1iqd	Human factor viii c2 domain complexed to human monoclonal bo2c11 fab.
1k3i	Crystal structure of the precursor of galactose oxidase
1kex	Crystal structure of the b1 domain of human neuropilin-1
1sdd	Crystal structure of bovine factor vai
1t2x	Glactose oxidase c383s mutant identified by directed evolution
1w8n	Contribution of the active site aspartic acid to catalysis in the bacterial neuraminidase from micromonospora viridifaciens.
1w8o	Contribution of the active site aspartic acid to catalysis in the bacterial neuraminidase from micromonospora viridifaciens
1wcq	Mutagenesis of the nucleophilic tyrosine in a bacterial sialidase to phenylalanine.
2ber	Y370g active site mutant of the sialidase from micromonospora viridifaciens in complex with beta-neu5ac (sialic acid).
2bzd	Galactose recognition by the carbohydrate-binding module of a bacterial sialidase.
2eib	Crystal structure of galactose oxidase, w290h mutant
2eic	Crystal structure of galactose oxidase mutant w290f
2eid	Galactose oxidase w290g mutant
2eie	Crystal structure of galactose oxidase complexed with azide
2jkx
2orx	Structural basis for ligand binding and heparin mediated activation of neuropilin
2orz	Structural basis for ligand binding and heparin mediated activation of neuropilin
2pqs	Crystal structure of the bovine lactadherin c2 domain
2qqi	Crystal structure of the b1b2 domains from human neuropilin-
2qqj	Crystal structure of the b1b2 domains from human neuropilin-
2qqk	Neuropilin-2 a1a2b1b2 domains in complex with a semaphorin- blocking fab
2qql	Neuropilin-2 a1a2b1b2 domains in complex with a semaphorin- blocking fab
2qqm	Crystal structure of the a2b1b2 domains from human neuropilin-1
2qqn	Neuropilin-1 b1 domain in complex with a vegf-blocking fab
2qqo	Crystal structure of the a2b1b2 domains from human neuropilin-2
2r7e	Crystal structure analysis of coagulation factor viii
2vm9	Native structure of the recombinant discoidin ii of dictyostelium discoideum at 1.75 angstrom
2vmc	Structure of the complex of discoidin ii from dictyostelium discoideum with n-acetyl-galactosamine
2vmd	Structure of the complex of discoidin ii from dictyostelium discoideum with beta-methyl-galactose
2vme	Structure of the wild-type discoidin ii from dictyostelium discoideum
2vz1
2vz3
2w1q
2w1s
2w1u
2wdb
2z4f	Solution structure of the discoidin domain of ddr2
3bn6	Crystal structure of the c2 domain of bovine lactadherin at 1.67 angstrom resolution
3cdz	Crystal structure of human factor viii

Links (links to other resources describing this domain)

• PFAM: F5_F8_type_C
• INTERPRO: IPR000421
• PROSITE: FA58C_2