| Structural highlights
6mf2 is a 1 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 3.609364Å |
| Ligands: | BMA, CA, CU1, NAG, ZN |
| 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
BACKGROUND: Coagulation factor VIII represents one of the oldest protein-based therapeutics, serving as an effective hemophilia A treatment for half a century. Optimal treatment consists of repeated intravenous infusions of blood coagulation factor VIII (FVIII) per week for life. Despite overall treatment success, significant limitations remain, including treatment invasiveness, duration, immunogenicity, and cost. These issues have inspired research into the development of bioengineered FVIII products and gene therapies. OBJECTIVES: To structurally characterize a bioengineered construct of FVIII, termed ET3i, which is a human/porcine chimeric B domain-deleted heterodimer with improved expression and slower A2 domain dissociation following proteolytic activation by thrombin. METHODS: The structure of ET3i was characterized with X-ray crystallography and tandem mass spectrometry-based glycoproteomics. RESULTS: Here, we report the 3.2 A crystal structure of ET3i and characterize the distribution of N-linked glycans with LC-MS/MS glycoproteomics. This structure shows remarkable conservation with the human FVIII protein and provides a detailed view of the interface between the A2 domain and the remaining FVIII structure. With two FVIII molecules in the crystal, we observe two conformations of the C2 domain relative to the remaining FVIII structure. The improved model and stereochemistry of ET3i served as a scaffold to generate an improved, refined structure of human FVIII. With the original datasets at 3.7 A and 4.0 A resolution, this new structure resulted in improved refinement statistics. CONCLUSIONS: These improved structures yield a more confident model for next-generation engineering efforts to develop FVIII therapeutics with longer half-lives, higher expression levels, and lower immunogenicity.
The 3.2 A structure of a bioengineered variant of blood coagulation factor VIII indicates two conformations of the C2 domain.,Smith IW, d'Aquino AE, Coyle CW, Fedanov A, Parker ET, Denning G, Spencer HT, Lollar P, Doering CB, Spiegel PC Jr J Thromb Haemost. 2019 Aug 27. doi: 10.1111/jth.14621. PMID:31454152[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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- ↑ 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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- ↑ 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
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- ↑ 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
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- ↑ 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
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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
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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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- ↑ 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
- ↑ 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
- ↑ Smith IW, d'Aquino AE, Coyle CW, Fedanov A, Parker ET, Denning G, Spencer HT, Lollar P, Doering CB, Spiegel PC Jr. The 3.2 A structure of a bioengineered variant of blood coagulation factor VIII indicates two conformations of the C2 domain. J Thromb Haemost. 2019 Aug 27. doi: 10.1111/jth.14621. PMID:31454152 doi:https://dx.doi.org/10.1111/jth.14621
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