1iqd is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
FA8_HUMAN Factor VIII, along with calcium and phospholipid, acts as a cofactor for factor IXa when it converts factor X to the activated form, factor Xa.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The development of an immune response to infused factor VIII is a complication affecting many patients with hemophilia A. Inhibitor antibodies bind to antigenic determinants on the factor VIII molecule and block its procoagulant activity. A patient-derived inhibitory immunoglobulin G4kappa antibody (BO2C11) produced by an immortalized memory B-lymphocyte cell line interferes with the binding of factor VIII to phospholipid surfaces and to von Willebrand factor. The structure of a Fab fragment derived from this antibody complexed with the factor VIII C2 domain was determined at 2.0 A resolution. The Fab interacts with solvent-exposed basic and hydrophobic side chains that form a membrane-association surface of factor VIII. This atomic resolution structure suggests a variety of amino acid substitutions in the C2 domain of factor VIII that might prevent the binding of anti-C2 inhibitor antibodies without significantly compromising the procoagulant functions of factor VIII.
Structure of a factor VIII C2 domain-immunoglobulin G4kappa Fab complex: identification of an inhibitory antibody epitope on the surface of factor VIII.,Spiegel PC Jr, Jacquemin M, Saint-Remy JM, Stoddard BL, Pratt KP Blood. 2001 Jul 1;98(1):13-9. PMID:11418455[79]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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↑Kogan S, Gitschier J. Mutations and a polymorphism in the factor VIII gene discovered by denaturing gradient gel electrophoresis. Proc Natl Acad Sci U S A. 1990 Mar;87(6):2092-6. PMID:2107542
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↑Schwaab R, Ludwig M, Kochhan L, Oldenburg J, McVey JH, Egli H, Brackmann HH, Olek K. Detection and characterisation of two missense mutations at a cleavage site in the factor VIII light chain. Thromb Res. 1991 Feb 1;61(3):225-34. PMID:1851341
↑Krepelova A, Vorlova Z, Acquila M, Mori P. GAA(Glu)272----AAA(Lys) and CGA(Arg)1941----CAA(Gln) in the factor VIII gene in two haemophilia A patients of Czech origin. Br J Haematol. 1992 Jul;81(3):458. PMID:1356412
↑Economou EP, Kazazian HH Jr, Antonarakis SE. Detection of mutations in the factor VIII gene using single-stranded conformational polymorphism (SSCP). Genomics. 1992 Jul;13(3):909-11. PMID:1639429
↑Reiner AP, Thompson AR. Screening for nonsense mutations in patients with severe hemophilia A can provide rapid, direct carrier detection. Hum Genet. 1992 Apr;89(1):88-94. PMID:1349567
↑Nafa K, Baudis M, Deburgrave N, Bardin JM, Sultan Y, Kaplan JC, Delpech M. A novel mutation (Arg-->Leu in exon 18) in factor VIII gene responsible for moderate hemophilia A. Hum Mutat. 1992;1(1):77-8. PMID:1301194 doi:https://dx.doi.org/10.1002/humu.1380010114
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↑McGinniss MJ, Kazazian HH Jr, Hoyer LW, Bi L, Inaba H, Antonarakis SE. Spectrum of mutations in CRM-positive and CRM-reduced hemophilia A. Genomics. 1993 Feb;15(2):392-8. PMID:8449505 doi:https://dx.doi.org/S0888-7543(83)71073-6
↑Pieneman WC, Reitsma PH, Briet E. Double strand conformation polymorphism (DSCP) detects two point mutations at codon 280 (AAC-->ATC) and at codon 431 (TAC-->AAC) of the blood coagulation factor VIII gene. Thromb Haemost. 1993 May 3;69(5):473-5. PMID:8322269
↑Arruda VR, Pieneman WC, Reitsma PH, Deutz-Terlouw PP, Annichino-Bizzacchi JM, Briet E, Costa FF. Eleven novel mutations in the factor VIII gene from Brazilian hemophilia A patients. Blood. 1995 Oct 15;86(8):3015-20. PMID:7579394
↑Pieneman WC, Deutz-Terlouw PP, Reitsma PH, Briet E. Screening for mutations in haemophilia A patients by multiplex PCR-SSCP, Southern blotting and RNA analysis: the detection of a genetic abnormality in the factor VIII gene in 30 out of 35 patients. Br J Haematol. 1995 Jun;90(2):442-9. PMID:7794769
↑Bidichandani SI, Lanyon WG, Shiach CR, Lowe GD, Connor JM. Detection of mutations in ectopic factor VIII transcripts from nine haemophilia A patients and the correlation with phenotype. Hum Genet. 1995 May;95(5):531-8. PMID:7759074
↑Becker J, Schwaab R, Moller-Taube A, Schwaab U, Schmidt W, Brackmann HH, Grimm T, Olek K, Oldenburg J. Characterization of the factor VIII defect in 147 patients with sporadic hemophilia A: family studies indicate a mutation type-dependent sex ratio of mutation frequencies. Am J Hum Genet. 1996 Apr;58(4):657-70. PMID:8644728
↑Chan V, Pang A, Chan TP, Chan VW, Chan TK. Molecular characterization of haemophilia A in southern Chinese. Br J Haematol. 1996 May;93(2):451-6. PMID:8639447
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↑Mazurier C, Gaucher C, Jorieux S, Parquet-Gernez A. Mutations in the FVIII gene in seven families with mild haemophilia A. Br J Haematol. 1997 Feb;96(2):426-7. PMID:9029040
↑Morichika S, Shima M, Kamisue S, Tanaka I, Imanaka Y, Suzuki H, Shibata H, Pemberton S, Gale K, McVey J, Tuddenham EG, Yoshioka A. Factor VIII gene analysis in Japanese CRM-positive and CRM-reduced haemophilia A patients by single-strand conformation polymorphism. Br J Haematol. 1997 Sep;98(4):901-6. PMID:9326186
↑Tavassoli K, Eigel A, Pollmann H, Horst J. Mutational analysis of ectopic factor VIII transcripts from hemophilia A patients: identification of cryptic splice site, exon skipping and novel point mutations. Hum Genet. 1997 Oct;100(5-6):508-11. PMID:9341862
↑Liu M, Murphy ME, Thompson AR. A domain mutations in 65 haemophilia A families and molecular modelling of dysfunctional factor VIII proteins. Br J Haematol. 1998 Dec;103(4):1051-60. PMID:9886318
↑Theophilus BD, Enayat MS, Higuchi M, Kazazian HH, Antonarakis SE, Hill FG. Independent occurrence of the novel Arg2163 to His mutation in the factor VIII gene in three unrelated families with haemophila A with different phenotypes. Mutations in brief no. 126. Online. Hum Mutat. 1998;11(4):334. PMID:10215414 doi:<334::AID-HUMU20>3.0.CO;2-# 10.1002/(SICI)1098-1004(1998)11:4<334::AID-HUMU20>3.0.CO;2-#
↑Tavassoli K, Eigel A, Dworniczak B, Valtseva E, Horst J. Identification of four novel mutations in the factor VIII gene: three missense mutations (E1875G, G2088S, I2185T) and a 2-bp deletion (1780delTC). Hum Mutat. 1998;Suppl 1:S260-2. PMID:9452104
↑Williams IJ, Abuzenadah A, Winship PR, Preston FE, Dolan G, Wright J, Peake IR, Goodeve AC. Precise carrier diagnosis in families with haemophilia A: use of conformation sensitive gel electrophoresis for mutation screening and polymorphism analysis. Thromb Haemost. 1998 Apr;79(4):723-6. PMID:9569180
↑Hay CR, Ludlam CA, Colvin BT, Hill FG, Preston FE, Wasseem N, Bagnall R, Peake IR, Berntorp E, Mauser Bunschoten EP, Fijnvandraat K, Kasper CK, White G, Santagostino E. Factor VIII inhibitors in mild and moderate-severity haemophilia A. UK Haemophilia Centre Directors Organisation. Thromb Haemost. 1998 Apr;79(4):762-6. PMID:9569189
↑Keeling DM, Sukhu K, Kemball-Cook G, Waseem N, Bagnall R, Lloyd JV. Diagnostic importance of the two-stage factor VIII:C assay demonstrated by a case of mild haemophilia associated with His1954-->Leu substitution in the factor VIII A3 domain. Br J Haematol. 1999 Jun;105(4):1123-6. PMID:10554831
↑Waseem NH, Bagnall R, Green PM, Giannelli F. Start of UK confidential haemophilia A database: analysis of 142 patients by solid phase fluorescent chemical cleavage of mismatch. Haemophilia Centres. Thromb Haemost. 1999 Jun;81(6):900-5. PMID:10404764
↑Jacquemin M, Lavend'homme R, Benhida A, Vanzieleghem B, d'Oiron R, Lavergne JM, Brackmann HH, Schwaab R, VandenDriessche T, Chuah MK, Hoylaerts M, Gilles JG, Peerlinck K, Vermylen J, Saint-Remy JM. A novel cause of mild/moderate hemophilia A: mutations scattered in the factor VIII C1 domain reduce factor VIII binding to von Willebrand factor. Blood. 2000 Aug 1;96(3):958-65. PMID:10910910
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↑Cutler JA, Mitchell MJ, Smith MP, Savidge GF. The identification and classification of 41 novel mutations in the factor VIII gene (F8C). Hum Mutat. 2002 Mar;19(3):274-8. PMID:11857744 doi:10.1002/humu.10056
↑Frusconi S, Passerini I, Girolami F, Masieri M, Linari S, Longo G, Morfini M, Torricelli F. Identification of seven novel mutations of F8C by DHPLC. Hum Mutat. 2002 Sep;20(3):231-2. PMID:12203998 doi:10.1002/humu.9052
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↑Cai XH, Wang XF, Dai J, Fang Y, Ding QL, Xie F, Wang HL. Female hemophilia A heterozygous for a de novo frameshift and a novel missense mutation of factor VIII. J Thromb Haemost. 2006 Sep;4(9):1969-74. Epub 2006 Jun 27. PMID:16805874 doi:JTH2105
↑Vencesla A, Corral-Rodriguez MA, Baena M, Cornet M, Domenech M, Baiget M, Fuentes-Prior P, Tizzano EF. Identification of 31 novel mutations in the F8 gene in Spanish hemophilia A patients: structural analysis of 20 missense mutations suggests new intermolecular binding sites. Blood. 2008 Apr 1;111(7):3468-78. doi: 10.1182/blood-2007-08-108068. Epub 2008, Jan 9. PMID:18184865 doi:10.1182/blood-2007-08-108068
↑Albanez S, Ruiz-Saez A, Boadas A, de Bosch N, Porco A. Identification of factor VIII gene mutations in patients with severe haemophilia A in Venezuela: identification of seven novel mutations. Haemophilia. 2011 Sep;17(5):e913-8. doi: 10.1111/j.1365-2516.2011.02500.x. Epub, 2011 Mar 4. PMID:21371196 doi:10.1111/j.1365-2516.2011.02500.x
↑Spiegel PC Jr, Jacquemin M, Saint-Remy JM, Stoddard BL, Pratt KP. Structure of a factor VIII C2 domain-immunoglobulin G4kappa Fab complex: identification of an inhibitory antibody epitope on the surface of factor VIII. Blood. 2001 Jul 1;98(1):13-9. PMID:11418455
