| 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
BACKGROUND: Coagulation factor (F)VIII is the inactive precursor of FVIIIa, an essential component of the intrinsic tenase complex. Despite numerous structures of recombinant FVIII in solution, the structural basis of the procofactor-membrane interface remains poorly defined. Traditional liposome platforms require special grids and often suffer from heterogeneous particle distribution and overcrowding, precluding high-resolution single-particle analysis (SPA), while membrane mimetics, nanodiscs, are too planar posing significant biophysical challenges. OBJECTIVES: To establish a reproducible methodology for structural determination of membrane-bound coagulation factors and resolve the procofactor FVIII-lipid interface. METHODS: We used methylated branched lipids to compensate for membrane planarity and employed cryo-EM to solve the structure of FVIII bound to lipids. RESULTS: We resolved the cryo-EM structure of procofactor FVIII on nanodiscs and liposomes lipid membranes at 3.46 - 3.56 A, respectively. Structural analysis reveals a definitive tilted docking orientation where both C domains mediate shallow interfacial insertion with the C2 domain acts as the primary anchor and the C1 domain serves as a secondary tether. This spatial arrangement structurally explains the high clinical severity of C2-interface mutations compared to more moderate C1 surface mutations. CONCLUSION: Methylated branched lipids enable rapid, high-resolution characterization of membrane-associated clotting factors. This structure provides the first definitive template for the FVIII-lipid interface, serving as a benchmark for future studies on tenase complex assembly.
Structural determination of lipid-bound Factor VIII.,Mohammed BM J Thromb Haemost. 2026 May 26:S1538-7836(26)00344-2. doi: , 10.1016/j.jtha.2026.05.021. PMID:42202884[79]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ 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
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- ↑ 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
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- ↑ 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
- ↑ Mohammed BM. Structural determination of lipid-bound factor VIII. J Thromb Haemost. 2026 May 26:S1538-7836(26)00344-2. PMID:42202884 doi:10.1016/j.jtha.2026.05.021
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