Structural Basis for Hemophilia A Caused by Mutations in the C Domains of Blood Coagulation Factor VIII

Andrew J. Gale; Jean-Luc Pellequer; Elizabeth D. Getzoff; John H. Griffin

doi:10.1055/s-0037-1613761

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2000; 83(01): 78-85
DOI: 10.1055/s-0037-1613761

Commentary

Schattauer GmbH

Structural Basis for Hemophilia A Caused by Mutations in the C Domains of Blood Coagulation Factor VIII

Andrew J. Gale

¹From the Departments of Molecular and Experimental Medicine and of Vascular Biology, The Scripps Research Institute, La Jolla, CA, USA

,

Jean-Luc Pellequer

²Department of Molecular Biology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA

,

Elizabeth D. Getzoff

²Department of Molecular Biology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA

,

John H. Griffin

¹From the Departments of Molecular and Experimental Medicine and of Vascular Biology, The Scripps Research Institute, La Jolla, CA, USA

› Author Affiliations

Abstract

Summary

Three dimensional homology models for the C1 and C2 domains of factor VIII (FVIII) were generated. Each C domain formed a β-sandwich, and C1 was covalently connected to C2 in a head-to-head orientation. Of the >250 missense mutations that cause FVIII deficiency and hemophilia A, 34 are in the C domains. We used the FVIII C1-C2 model to infer the structural basis for the pathologic effects of these mutations. The mutated residues were divided into four categories: 15 conserved buried residues that affect normal packing of the hydrophobic side chains, 2 non-conserved buried residues that affect structure, 11 conserved exposed residues and 6 non-conserved exposed residues. The effects of all 34 missense mutations can be rationalized by predictable disruptions of FVIII structure while at most four mutations (S2069F, T2154I, R2209Q/G/L and E2181D) may affect residues directly involved in intermolecular interactions of FVIII/VIIIa with other coagulation factors or vWF.

Key words

Hemophilia A - Factor VIII - homology modeling - von Willebrand factor - coagulation

Full Text

References

References
1 Kazazian HHJ, Tuddenham EGD, Antonarakis SE. Hemophilia A and parahemophilia: Deficiencies of coagulation factors VIII and V. In: The Metabolic and Molecular Bases of Inherited Disease. Scriver CR, Beaudet AL, Sly WS, Valle D. eds. New York, New York: McGraw-Hill Inc; 1995: 3241-67.
2 Lenting PJ, van Mourik JA, Mertens K. The life cycle of coagulation factor VIII in view of its structure and function. Blood 1998; 92: 3983-96.
3 Kane WH, Davie EW. Blood coagulation factors V and VIII: Structural and functional similarities and their relationship to hemorrhagic and thrombotic disorders. Blood 1988; 71: 539-55.
4 Toole JJ, Knopf JL, Wozney JM, Sultzman LA, Buecker JL, Pittman DD, Kaufman RJ, Brown E, Shoemaker C, Orr EC. Molecular cloning of a cDNA encoding human antihaemophilic factor. Nature 1984; 312: 342-7.
5 Wood WI, Capon DJ, Simonsen CC, Eaton DL, Gitschier J, Keyt B, Seeburg PH, Smith DH, Hollingshead P, Wion KL. Expression of active human factor VIII from recombinant DNA clones. Nature 1984; 312: 330-7.
6 Gitschier J, Wood WI, Goralka TM, Wion KL, Chen EY, Eaton DH, Vehar GA, Capon DJ, Lawn RM. Characterization of the human factor VIII gene. Nature 1984; 312: 326-30.
7 Vehar GA, Keyt B, Eaton D, Rodriguez H, O’Brien DP, Rotblat F, Oppermann H, Keck R, Wood WI, Harkins RN. Structure of human factor VIII. Nature 1984; 312: 337-42.
8 Church WR, Jernigan RL, Toole J, Hewick RM, Knopf J, Knutson GJ, Nesheim ME, Mann KG, Fass DN. Coagulation factors V and VIII and ceruloplasmin constitute a family of structurally related proteins. Proc Natl Acad Sci USA 1984; 81: 6934-7.
9 Baumgartner S, Hofmann K, Chiquet-Ehrismann R, Bucher P. The discoidin domain family revisited: new members from prokaryotes and a homology-based fold prediction. Protein Sci 1998; 07: 1626-31.
10 Pan Y, DeFay T, Gitschier J, Cohen FE. Proposed structure of the A domains of factor VIII by homology modelling. Nature Struct Biol 1995; 02: 740-4.
11 Pemberton S, Lindley P, Zaitsev V, Card G, Tuddenham EGD, Kemball-Cook G. A molecular model for the triplicated A domains of human factor VIII based on the crystal structure of human ceruloplasmin. Blood 1997; 89: 2413-21.
12 Pellequer JL, Gale AJ, Griffin JH, Getzoff ED. Homology modeling of factor Va, a cofactor of the prothrombinase complex. Protein Sci 1998; 07: 159.
13 Villoutreix BO, Dahlbäck B. Structural investigation of the A domains of human blood coagulation factor V by molecular modeling. Protein Sci 1998; 07: 1317-25.
14 Pellequer JL, Gale AJ, Griffin JH, Getzoff ED. Homology models of the C domains of blood coagulation factors V and VIII: A proposed membrane binding mode for FV and FVIII C2 domains. Blood Cells Mol Dis 1998; 24: 448-61.
15 Villoutreix BO, Bucher P, Hofmann K, Baumgartner S, Dahlbäck B. Molecular models for the two discoidin domains of human blood coagulation factor V. J Mol Model 1998; 04: 268-75.
16 Greer J. Comparative modeling methods: Application to the family of the mammalian serine proteases. Proteins 1990; 07: 317-34.
17 Tuffery P, Etchebest C, Hazout S, Lavery R. A new approach to the rapid determination of protein side chain conformations. J Biomol Struct Dyn 1991; 08: 1267-89.
18 Roussel A, Cambillau C. TURBO-FRODO: Silicon Graphics geometry partners directory. Mountain View, California, Silicon Graphics. 1989
19 Brünger AT. X-PLOR Manual. Version 3.0. New Haven: Yale University; 1992
20 Brooks B, Bruccoleri R, Olafson B, States D, Swaminathan S, Karplus M. CHARMM: A program for macromolecular energy minimization, and molecular dynamics calculations. J Comp Chem 1983; 04: 187-217.
21 Kemball-Cook G, Tuddenham EGD, Wacey AI. The factor VIII Structure and Mutation Resource Site: HAMSTeRS version 4. Nucleic Acids Res 1998; 26: 216-9.
22 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; 79: 723-6.
23 Poteete AR, Rennell D, Bouvier SE. Functional significance of conserved amino acid residues. Proteins 1992; 13: 38-40.
24 Laskowski RA, MacArthur MW, Moss DS, Thornton JM. PROCHECK: A program to check the stereochemical quality of protein structures. J Appl Cryst 1993; 26: 283-91.
25 Pratt KP, Fujikawa K, Takeshima K, Davie EW, Stoddard BS. Crystal structure of the factor VIII C2 domain. Thromb Haemost 1999; Suppl: 234.
26 Sauer RT, Milla ME, Waldburger CD, Brown BM, Schildbach JF. Sequence determinants of folding and stability for the P22 Arc repressor dimer. FASEB J 1996; 10: 42-8.
27 Matthews BW. Structural and genetic analysis of the folding and function of T4 lysozyme. FASEB J 1996; 10: 35-41.
28 Chothia C. Hydrophobic bonding and accessible surface area in proteins. Nature 1974; 248: 338-9.
29 Lim WA, Farruggio DC, Sauer RT. Structural and energetic consequences of disruptive mutations in a protein core. Biochemistry 1992; 31: 4324-33.
30 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: 301-3.
31 Kim SW, Quinn-Allen M-A, Kane WH. Indentification of functionally important amino acid residues within the C2 domain of human factor V using alanine scanning mutagenesis. Blood 1998; 92: 184a-5a.
32 Casula L, Murru S, Pecorara M, Ristaldi MS, Restagno G, Mancuso G, Morfini M, De Biasi R, Baudo F, Carbonara A. Recurrent mutations and three novel rearrangements in the factor VIII gene of hemophilia A patients of Italian descent. Blood 1990; 75: 662-70.
33 Schwaab R, Oldenburg J, Tuddenham EG, Brackmann HH, Olek K. Mutations in haemophilia A. Br J Haematol 1993; 83: 450-8.
34 Millar DS, Zoll B, Martinowitz U, Kakkar VV, Cooper DN. The molecular genetics of haemophilia A: screening for point mutations in the factor VIII gene using the restriction enzyme TaqI. Hum Genet 1991; 87: 607-12.
35 Figueiredo MS, Tavella MH, Simoes BP. Large DNA inversions, deletions, and TaqI site mutations in severe haemophilia A. Hum Genet 1994; 94: 473-8.
36 Pipe SW, Kaufman RJ. Factor VIII C2 domain missense mutations exhibit defective trafficking of biologically functional proteins. J Biol Chem 1996; 271: 25671-6.
37 Voorberg J, de Laaf RT, Koster PM, van Mourik JA. Intracellular retention of a factor VIII protein with an Arg2307→Gln mutation as a cause of haemophilia A. Biochem J 1996; 318: 931-7.
38 Hurtley SM, Helenius A. Protein oligomerization in the endoplasmic reticulum. Annu Rev Cell Biol 1989; 05: 277-307.
39 Rose JK, Doms RW. Regulation of protein export from the endoplasmic reticulum. Annu Rev Cell Biol 1988; 04: 257-88.
40 Sommer T, Wolf DH. Endoplasmic reticulum degradation: reverse protein flow of no return. FASEB J 1997; 11: 1227-33.
41 Sturtevant JM, Yu MH, Haase-Pettingell C, King J. Thermostability of temperature-sensitive folding mutants of the P22 tailspike protein. J Biol Chem 1989; 264: 10693-8.
42 Villafane R, King J. Nature and distribution of sites of temperature-sensitive folding mutations in the gene for the P22 tailspike polypeptide chain. J Mol Biol 1988; 204: 607-19.
43 Yu MH, King J. Surface amino acids as sites of temperature-sensitive folding mutations in the P22 tailspike protein. J Biol Chem 1988; 263: 1424-31.
44 Foster PA, Fulcher CA, Houghten RA, Zimmerman TS. An immunogenic region within residues Val1670-Glu1684 of the factor VIII light chain induces antibodies which inhibit binding of factor VIII to von Willebrand factor. J Biol Chem 1988; 263: 5230-4.
45 Lollar P, Hill-Eubanks DC, Parker CG. Association of the factor VIII light chain with von Willebrand factor. J Biol Chem 1988; 263: 10451-5.
46 Saenko EL, Scandella D. The acidic region of the factor VIII light chain and the C2 domain together form the high affinity binding site for von Willebrand factor. J Biol Chem 1997; 272: 18007-14.
47 Nesheim ME, Pittman DD, Wang JH, Slonosky D, Giles AR, Kaufman RJ. The binding of 35S-labeled recombinant factor VIII to activated and unactivated human platelets. J Biol Chem 1988; 263: 16467-70.
48 Bloom JW. The interaction of rDNA factor VIII, factor VIIIdes-797-1562 and factor VIIIdes-797-1562-derived peptides with phospholipid. Thromb Res 1987; 48: 439-48.
49 Foster PA, Fulcher CA, Houghten RA, Zimmerman TS. Synthetic factor VIII peptides with amino acid sequences contained within the C2 domain of factor VIII inhibit factor VIII binding to phosphatidylserine. Blood 1990; 75: 1999-2004.
50 Arai M, Scandella D, Hoyer LW. Molecular basis of factor VIII inhibition by human antibodies. Antibodies that bind to the factor VIII light chain prevent the interaction of factor VIII with phospholipid. J Clin Invest 1989; 83: 1978-84.
51 Andersson LO, Brown JE. Interaction of factor VIII-von Willebrand Factor with phospholipid vesicles. Biochem J 1981; 200: 161-7.
52 Fay PJ, Coumans JV, Walker FJ. von Willebrand factor mediates protection of factor VIII from activated protein C-catalyzed inactivation. J Biol Chem 1991; 266: 2172-7.
53 Saenko EL, Shima M, Rajalakshmi KJ, Scandella D. A role for the C2 domain of factor VIII in binding to von Willebrand factor. J Biol Chem 1994; 269: 11601-5.
54 Scandella D, Gilbert GE, Shima M, Nakai H, Eagleson C, Felch M, Prescott R, Rajalakshmi KJ, Hoyer LW, Saenko E. Some factor VIII inhibitor antibodies recognize a common epitope corresponding to C2 domain amino acids 2248 through 2312, which overlap a phospholipid-binding site. Blood 1995; 86: 1811-9.
55 Shima M, Scandella D, Yoshioka A, Nakai H, Tanaka I, Kamisue S, Terada S, Fukui H. A factor VIII neutralizing monoclonal antibody and a human inhibitor alloantibody recognizing epitopes in the C2 domain inhibit factor VIII binding to von Willebrand factor and to phosphatidylserine. Thromb Haemost 1993; 69: 240-6.
56 Healey JF, Barrow RT, Tamim HM, Lubin IM, Shima M, Scandella D, Lollar P. Residues Glu2181-Val2243 contain a major determinant of the inhibitory epitope in the C2 domain of human factor VIII. Blood 1998; 92: 3701-9.
57 Diamond C, Kogan S, Levinson B, Gitschier J. Amino acid substitutions in conserved domains of factor VIII and related proteins: study of patients with mild and moderately severe hemophilia A. Hum Mutat 1992; 01: 248-57.
58 Schwaab R, Oldenburg J, Schwaab U, Johnson DJ, Schmidt W, Olek K, Brackman HH, Tuddenham EG. Characterization of mutations within the factor VIII gene of 73 unrelated mild and moderate haemophiliacs. Br J Haematol 1995; 91: 458-64.
59 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; 100: 508-11.
60 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. 01) S260-S2.
61 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; 90: 442-9.
62 Higuchi M, Antonarakis SE, Kasch L, Oldenburg J, Economou-Petersen E, Olek K, Arai M, Inaba H, Kazazian HHJ. Molecular characterization of mild-to-moderate hemophilia A: detection of the mutation in 25 of 29 patients by denaturing gradient gel electrophoresis. Proc Natl Acad Sci USA 1991; 88: 8307-11.
63 Naylor JA, Green PM, Rizza CR, Giannelli F. Analysis of factor VIII mRNA reveals defects in everyone of 28 haemophilia A patients. Hum Mol Genet 1993; 02: 11-7.
64 Levinson B, Janco R, Phillips J, Gitschier J. A novel missense mutation in the factor VIII gene identified by analysis of amplified hemophilia DNA sequences. Nucleic Acids Res 1987; 15: 9797-805.
65 Jonsdottir S, Diamond C, Levinson B, Magnusson S, Jensson O, Gitschier J. Missense mutations causing mild hemophilia A in Iceland detected by denaturing gradient gel electrophoresis. Hum Mutat 1992; 01: 506-8.
66 Reiner AP, Stray SM, Thompson AR. Three missense mutations in Arg codons of the factor VIII genes of mild to moderately severe hemophilia A patients. Thromb Res 1992; 66: 93-9.
67 Hay CR. Factor VIII inhibitors in mild and moderate-severity haemophilia A. Haemophilia 1998; 04: 558-63.
68 Levinson B, Lehesjoki AE, De La Chapelle A, Gitschier J. Molecular analysis of hemophilia A mutations in the Finnish population. Am J Hum Genet 1990; 46: 53-62.
69 Lin SW, Lin SR, Shen MC. Characterization of genetic defects of hemophilia A in patients of Chinese origin. Genomics 1993; 18: 496-504.
70 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; 98: 901-6.
71 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; 86: 3015-20.
72 Liao D-I, Remington SJ. Structure of wheat serine carboxypeptidase II at 3.5-Å resolution. A new class of serine proteinase. J Biol Chem 1990; 265: 6528-31.
73 Higuchi M, Kazazian HHJ, Kasch L, Warren TC, McGinniss MJ, Phillips JA, Kasper C, Janco R, Antonarakis SE. Molecular characterization of severe hemophilia A suggests that about half the mutations are not within the coding regions and splice junctions of the factor VIII gene. Proc Natl Acad Sci USA 1991; 88: 7405-9.
74 Paynton C, Sarkar G, Sommer SS. Identification of mutations in two families with sporadic hemophilia A. Hum Genet 1991; 87: 397-400.
75 Inaba H, Fujimaki M, Kazazian HHJ, Antonarakis SE. Mild hemophilia A resulting from Arg-to-Leu substitution in exon 26 of the factor VIII gene. Hum Genet 1989; 81: 335-8.
76 Gitschier J, Wood WI, Shuman MA, Lawn RM. Identification of a missense mutation in the factor VIII gene of a mild hemophiliac. Science 1986; 232: 1415-6.
77 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; 58: 657-70.
78 Kraulis PJ. MOLSCRIPT: A program to produce both detailed and schematic plots of protein structures. J Appl Cryst 1991; 24: 946-50.
79 Merritt EA, Bacon DJ. Raster3D: Photorealistic molecular graphics. Methods Enzymol 1997; 277: 505-24.