| Structural highlights
5k8d is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 4.19Å |
| Ligands: | BMA, CA, CU, MAN, NAG |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
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
Essentials Recombinant factor VIII (rFVIII) Fc fusion protein has a 1.5-fold longer half-life than rFVIII. Five orthogonal methods were used to characterize the structure of rFVIIIFc compared to rFVIII. The C-terminal Fc fusion does not perturb the structure of FVIII in rFVIIIFc. The FVIII and Fc components of rFVIIIFc are flexibly tethered and functionally independent. SUMMARY: Background Fusion of the human IgG1 Fc domain to the C-terminal C2 domain of B-domain-deleted (BDD) factor VIII (FVIII) results in the recombinant FVIII Fc (rFVIIIFc) fusion protein, which has a 1.5-fold longer half-life in humans. Objective To assess the structural properties of rFVIIIFc by comparing its constituent FVIII and Fc elements with their respective isolated components, and evaluating their structural independence within rFVIIIFc. Methods rFVIIIFc and its isolated FVIII and Fc components were compared by the use of hydrogen-deuterium exchange mass spectrometry (HDX-MS). The structure of rFVIIIFc was also evaluated by the use of X-ray crystallography, small-angle X-ray scattering (SAXS), and electron microscopy (EM). The degree of steric interference by the appended Fc domain was assessed by EM and surface plasmon resonance (SPR). Results HDX-MS analysis of rFVIIIFc revealed that fusion caused no structural perturbations in FVIII or Fc. The rFVIIIFc crystal structure showed that the FVIII component is indistinguishable from published BDD FVIII structures. The Fc domain was not observed, indicating high mobility. SAXS analysis was consistent with an ensemble of rigid-body models in which the Fc domain exists in a largely extended orientation relative to FVIII. Binding of Fab fragments of anti-C2 domain antibodies to BDD FVIII was visualized by EM, and the affinities of the corresponding intact antibodies for BDD FVIII and rFVIIIFc were comparable by SPR analysis. Conclusions The FVIII and Fc components of rFVIIIFc are structurally indistinguishable from their isolated constituents, and show a high degree of structural independence, consistent with the functional comparability of rFVIIIFc and unmodified FVIII.
The structural basis for the functional comparability of factor VIII and the long-acting variant recombinant factor VIII Fc fusion protein.,Leksa NC, Chiu PL, Bou-Assaf GM, Quan C, Liu Z, Goodman AB, Chambers MG, Tsutakawa SE, Hammel M, Peters RT, Walz T, Kulman JD J Thromb Haemost. 2017 Jun;15(6):1167-1179. doi: 10.1111/jth.13700. Epub 2017 May, 3. PMID:28397397[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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- ↑ O'Brien DP, Tuddenham EG. Purification and characterization of factor VIII 1,689-Cys: a nonfunctional cofactor occurring in a patient with severe hemophilia A. Blood. 1989 Jun;73(8):2117-22. PMID:2499363
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- ↑ 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
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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
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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
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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-#
- ↑ Freson K, Peerlinck K, Aguirre T, Arnout J, Vermylen J, Cassiman JJ, Matthijs G. Fluorescent chemical cleavage of mismatches for efficient screening of the factor VIII gene. Hum Mutat. 1998;11(6):470-9. PMID:9603440 doi:<470::AID-HUMU8>3.0.CO;2-A 10.1002/(SICI)1098-1004(1998)11:6<470::AID-HUMU8>3.0.CO;2-A
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
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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
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- ↑ Schwaab R, Oldenburg J, Kemball-Cook G, Albert T, Juhler C, Hanfland P, Ingerslev J. Assay discrepancy in mild haemophilia A due to a factor VIII missense mutation (Asn694Ile) in a large Danish family. Br J Haematol. 2000 Jun;109(3):523-8. PMID:10886198
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- ↑ 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
- ↑ Leksa NC, Chiu PL, Bou-Assaf GM, Quan C, Liu Z, Goodman AB, Chambers MG, Tsutakawa SE, Hammel M, Peters RT, Walz T, Kulman JD. The structural basis for the functional comparability of factor VIII and the long-acting variant recombinant factor VIII Fc fusion protein. J Thromb Haemost. 2017 Jun;15(6):1167-1179. doi: 10.1111/jth.13700. Epub 2017 May, 3. PMID:28397397 doi:https://dx.doi.org/10.1111/jth.13700
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