| Structural highlights
Disease
[FA8_HUMAN] Defects in F8 are the cause of hemophilia A (HEMA) [MIM:306700]. A disorder of blood coagulation characterized by a permanent tendency to hemorrhage. About 50% of patients have severe hemophilia resulting in frequent spontaneous bleeding into joints, muscles and internal organs. Less severe forms are characterized by bleeding after trauma or surgery. Note=Of particular interest for the understanding of the function of F8 is the category of CRM (cross-reacting material) positive patients (approximately 5%) that have considerable amount of F8 in their plasma (at least 30% of normal), but the protein is non-functional; i.e. the F8 activity is much less than the plasma protein level. CRM-reduced is another category of patients in which the F8C antigen and activity are reduced to approximately the same level. Most mutations are CRM negative, and probably affect the folding and stability of the protein.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] [70] [71] [72] [73] [74] [75] [76] [77] [78]
Function
[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.
Publication Abstract from PubMed
Factor VIII binds to cell membranes prior to assembling with the serine protease, factor IXa, to form the factor X-activating enzyme complex. In order to better understand the interaction between factor VIII and phosphatidylserine-containing membranes, we have synthesized the membrane-binding peptide from the C2 domain of factor VIII, corresponding to residues 2303-2324. The peptide, fVIII2303-24, with a primary structure of TRYLRIHPQSWVHQIALRMEVL, aggregates at concentrations above 2 microM at pH 7 but is soluble at pH 6. fVIII2303-24 competes with fluorescein-labeled factor VIII (Ki = 3 microM) for binding sites on synthetic phosphatidylserine-containing membranes and for binding sites on stimulated platelets. Circular dichroism spectra indicate that fVIII2303-24 is predominantly a random coil in aqueous solution but adopts a predominantly helical conformation upon interaction with SDS micelles. 1H NMR spectroscopy in the presence of SDS micelles allowed estimation of interproton distances from the nuclear Overhauser effect and estimation of torsion angles from coupling constants indicated by splitting of resonance lines. The distance and angle estimates, processed by distance geometry/simulated annealing software, indicate that fVIII2303-24 has an alpha-helical segment encompassing residues P8-E20 and an extended segment encompassing residues L4-P8. The location of six hydrophobic residues on one face of the structure suggests that hydrophobic interactions contribute to membrane-binding. In addition, two arginines penetrate the hydrophobic plane suggesting that they interact with phosphate moieties in a phospholipid bilayer.
Membrane-binding peptide from the C2 domain of factor VIII forms an amphipathic structure as determined by NMR spectroscopy.,Gilbert GE, Baleja JD Biochemistry. 1995 Mar 7;34(9):3022-31. PMID:7893714[79]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
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- ↑ Levinson B, Janco R, Phillips J 3rd, Gitschier J. A novel missense mutation in the factor VIII gene identified by analysis of amplified hemophilia DNA sequences. Nucleic Acids Res. 1987 Dec 10;15(23):9797-805. PMID:3122181
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- ↑ 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-#
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- ↑ 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
- ↑ Tavassoli K, Eigel A, Wilke K, Pollmann H, Horst J. Molecular diagnostics of 15 hemophilia A patients: characterization of eight novel mutations in the factor VIII gene, two of which result in exon skipping. Hum Mutat. 1998;12(5):301-3. PMID:9792405 doi:<301::AID-HUMU2>3.0.CO;2-G 10.1002/(SICI)1098-1004(1998)12:5<301::AID-HUMU2>3.0.CO;2-G
- ↑ Laprise SL, Mak EK, Killoran KA, Layman LC, Gray MR. Use of denaturing gradient gel blots to screen for point mutations in the factor VIII gene. Hum Mutat. 1998;12(6):393-402. PMID:9829908 doi:<393::AID-HUMU5>3.0.CO;2-A 10.1002/(SICI)1098-1004(1998)12:6<393::AID-HUMU5>3.0.CO;2-A
- ↑ 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
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- ↑ 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
- ↑ Strmecki L, Benedik-Dolnicar M, Vouk K, Komel R. Screen of 55 Slovenian haemophilia A patients: identification of 2 novel mutations (S-1R and IVS23+1G-->A) and discussion of mutation spectrum. Mutation in brief no. 241. Online. Hum Mutat. 1999;13(5):413. PMID:10338101 doi:<413::AID-HUMU14>3.0.CO;2-H 10.1002/(SICI)1098-1004(1999)13:5<413::AID-HUMU14>3.0.CO;2-H
- ↑ Moller-Morlang K, Tavassoli K, Eigel A, Pollmann H, Horst J. Mutational-screening in the factor VIII gene resulting in the identification of three novel mutations, one of which is a donor splice mutation. Mutations in brief no. 245. Online. Hum Mutat. 1999;13(6):504. PMID:10408784 doi:<504::AID-HUMU14>3.0.CO;2-9 10.1002/(SICI)1098-1004(1999)13:6<504::AID-HUMU14>3.0.CO;2-9
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- ↑ Liu ML, Shen BW, Nakaya S, Pratt KP, Fujikawa K, Davie EW, Stoddard BL, Thompson AR. Hemophilic factor VIII C1- and C2-domain missense mutations and their modeling to the 1.5-angstrom human C2-domain crystal structure. Blood. 2000 Aug 1;96(3):979-87. PMID:10910913
- ↑ Roelse JC, De Laaf RT, Timmermans SM, Peters M, Van Mourik JA, Voorberg J. Intracellular accumulation of factor VIII induced by missense mutations Arg593-->Cys and Asn618-->Ser explains cross-reacting material-reduced haemophilia A. Br J Haematol. 2000 Feb;108(2):241-6. PMID:10691849
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- ↑ Vidal F, Farssac E, Altisent C, Puig L, Gallardo D. Rapid hemophilia A molecular diagnosis by a simple DNA sequencing procedure: identification of 14 novel mutations. Thromb Haemost. 2001 Apr;85(4):580-3. PMID:11341489
- ↑ Valleix S, Vinciguerra C, Lavergne JM, Leuer M, Delpech M, Negrier C. Skewed X-chromosome inactivation in monochorionic diamniotic twin sisters results in severe and mild hemophilia A. Blood. 2002 Oct 15;100(8):3034-6. PMID:12351418 doi:10.1182/blood-2002-01-0277
- ↑ Mazurier C, Parquet-Gernez A, Gaucher C, Lavergne JM, Goudemand J. Factor VIII deficiency not induced by FVIII gene mutation in a female first cousin of two brothers with haemophilia A. Br J Haematol. 2002 Nov;119(2):390-2. PMID:12406074
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- ↑ Citron M, Godmilow L, Ganguly T, Ganguly A. High throughput mutation screening of the factor VIII gene (F8C) in hemophilia A: 37 novel mutations and genotype-phenotype correlation. Hum Mutat. 2002 Oct;20(4):267-74. PMID:12325022 doi:10.1002/humu.10119
- ↑ Liu ML, Nakaya S, Thompson AR. Non-inversion factor VIII mutations in 80 hemophilia A families including 24 with alloimmune responses. Thromb Haemost. 2002 Feb;87(2):273-6. PMID:11858487
- ↑ Klopp N, Oldenburg J, Uen C, Schneppenheim R, Graw J. 11 hemophilia A patients without mutations in the factor VIII encoding gene. Thromb Haemost. 2002 Aug;88(2):357-60. PMID:12195713
- ↑ Bicocchi MP, Pasino M, Lanza T, Bottini F, Boeri E, Mori PG, Molinari AC, Rosano C, Acquila M. Analysis of 18 novel mutations in the factor VIII gene. Br J Haematol. 2003 Sep;122(5):810-7. PMID:12930394
- ↑ Habart D, Kalabova D, Novotny M, Vorlova Z. Thirty-four novel mutations detected in factor VIII gene by multiplex CSGE: modeling of 13 novel amino acid substitutions. J Thromb Haemost. 2003 Apr;1(4):773-81. PMID:12871415
- ↑ Yenchitsomanus P, Akkarapatumwong V, Pung-Amritt P, Intorasoot S, Thanootarakul P, Oranwiroon S, Veerakul G, Mahasandana C. Genotype and phenotype of haemophilia A in Thai patients. Haemophilia. 2003 Mar;9(2):179-86. PMID:12614369
- ↑ Bicocchi MP, Pasino M, Lanza T, Bottini F, Molinari AC, Caprino D, Rosano C, Acquila M. Small FVIII gene rearrangements in 18 hemophilia A patients: five novel mutations. Am J Hematol. 2005 Feb;78(2):117-22. PMID:15682412 doi:10.1002/ajh.20234
- ↑ Hill M, Deam S, Gordon B, Dolan G. Mutation analysis in 51 patients with haemophilia A: report of 10 novel mutations and correlations between genotype and clinical phenotype. Haemophilia. 2005 Mar;11(2):133-41. PMID:15810915 doi:10.1111/j.1365-2516.2005.01069.x
- ↑ 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
- ↑ Gilbert GE, Baleja JD. Membrane-binding peptide from the C2 domain of factor VIII forms an amphipathic structure as determined by NMR spectroscopy. Biochemistry. 1995 Mar 7;34(9):3022-31. PMID:7893714
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