Fig. 2.
Fig. 2. The factor VIII protein. Mature factor VIII consists of 2332 amino acids, which are arranged in a discrete domain structure: A1 (residues 1-336), A2 (373-710), B (741-1648), A3 (1690-2019), C1 (2020-2172), and C2 (2173-2332). The A domains are bordered by acidic regions a1 (337-372), a2 (711-740), and a3(1649-1689). Disulfide Bridges: Using B-domainless factor VIII, seven disulfide bonds have been identified: residues 153 and 179, 248 and 329 (A1 domain), 528 and 554, 630 and 711 (A2 domain), 1832 and 1858, 1899 and 1903 (A3 domain), and 2021 and 2169 (C1 domain).196Within the C2 domain, residues 2174 and 2326 most likely also form a disulfide bridge. Free cysteine-residues have been identified at positions 310, 692, and 2000.196 Cys528 and Cys1858 may be present as free cysteines, because these residues are reactive toward a sulfhydryl-specific fluorphor.197 With regard to the Cys-residues in the B-domain it is unknown whether they are free or linked.N-Linked Glycosylation: Factor VIII contains 25 consensus sequences (Asn-Xxx-Thr/Ser) that allow N-linked glycosylation. Using either full-length or B-domainless factor VIII, the majority of these sites have been shown to be glycosylated: residues 42 and 239 (A1 domain), residues 757, 784, 828, 900, 963, 1001, 1005, 1055, 1066, 1185, 1255, 1259, 1282, 1300, 1412, and 1442 (B domain), residue 1810 (A3 domain), and residue 2118 (C2 domain).198-200Nonglycosylated residues are present at positions 943 and 1384 (B domain) and at position 1685 (a3 acidic region). Residue 582 (A2 domain) has been reported to be nonglycosylated in two studies,199200 whereas one study reported this residue to be partially glycosylated.198 Finally, it remains to be investigated whether residue 1512 (B domain) is glycosylated. Tyrosine Sulfation: The acidic regions contain consensus sequences that allow sulfation of Tyr-residues at positions 346 (a1 region), 718, 719, 723 (a2 region), 1664, and 1680 (a3 region). Analysis using recombinant proteins established that all sites indeed can be sulfated.

The factor VIII protein. Mature factor VIII consists of 2332 amino acids, which are arranged in a discrete domain structure: A1 (residues 1-336), A2 (373-710), B (741-1648), A3 (1690-2019), C1 (2020-2172), and C2 (2173-2332). The A domains are bordered by acidic regions a1 (337-372), a2 (711-740), and a3(1649-1689). Disulfide Bridges: Using B-domainless factor VIII, seven disulfide bonds have been identified: residues 153 and 179, 248 and 329 (A1 domain), 528 and 554, 630 and 711 (A2 domain), 1832 and 1858, 1899 and 1903 (A3 domain), and 2021 and 2169 (C1 domain).196Within the C2 domain, residues 2174 and 2326 most likely also form a disulfide bridge. Free cysteine-residues have been identified at positions 310, 692, and 2000.196 Cys528 and Cys1858 may be present as free cysteines, because these residues are reactive toward a sulfhydryl-specific fluorphor.197 With regard to the Cys-residues in the B-domain it is unknown whether they are free or linked.N-Linked Glycosylation: Factor VIII contains 25 consensus sequences (Asn-Xxx-Thr/Ser) that allow N-linked glycosylation. Using either full-length or B-domainless factor VIII, the majority of these sites have been shown to be glycosylated: residues 42 and 239 (A1 domain), residues 757, 784, 828, 900, 963, 1001, 1005, 1055, 1066, 1185, 1255, 1259, 1282, 1300, 1412, and 1442 (B domain), residue 1810 (A3 domain), and residue 2118 (C2 domain).198-200Nonglycosylated residues are present at positions 943 and 1384 (B domain) and at position 1685 (a3 acidic region). Residue 582 (A2 domain) has been reported to be nonglycosylated in two studies,199,200 whereas one study reported this residue to be partially glycosylated.198 Finally, it remains to be investigated whether residue 1512 (B domain) is glycosylated. Tyrosine Sulfation: The acidic regions contain consensus sequences that allow sulfation of Tyr-residues at positions 346 (a1 region), 718, 719, 723 (a2 region), 1664, and 1680 (a3 region). Analysis using recombinant proteins established that all sites indeed can be sulfated.

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