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Molecular modeling of the von Willebrand factor A2 Domain and the effects of associated type 2A von Willebrand disease mutations

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Abstract

A homology model for the A2 domain of von Willebrand factor (VWF) is presented. A large number of target–template alignments were combined into a consensus alignment and used for constructing the model from the structures of six template proteins. Molecular dynamics simulation was used to study the structural and dynamic effects of eight mutations introduced into the model, all associated with type 2A von Willebrand disease. It was found that the group I mutations G1505R, L1540P and S1506L cause significant deviations over multiple regions of the protein, coupled to significant thermal fluctuations for G1505R and L1540P. This suggests that protein instability may be responsible for their intracellular retention. The group II mutations R1597W, E1638K and G1505E caused single loop displacements near the physiologic VWF proteolysis site between Y1605–M1606. These modest structural changes may affect interactions between VWF and the ADAMTS13 protease. The group II mutations I1628T and L1503Q caused no significant structural change in the protein, suggesting that inclusion of the protease in this model is necessary for understanding their effect.

Figure Homology model of the von Willebrand factor A2 domain

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References

  1. Sadler JE (1991) J Biol Chem 266:22777–22780

    CAS  PubMed  Google Scholar 

  2. Ruggeri ZM, Ware J (1992) Thromb Haemost 67:594–599

    CAS  PubMed  Google Scholar 

  3. Berliner S, Niiya K, Roberts JR, Houghten RA, Ruggeri ZM (1988) J Biol Chem 263:7500–7505

    CAS  PubMed  Google Scholar 

  4. Voorberg J, Fontijn R, Calafat J, Janssen H, van Mourik JA, Pannekoek H (1991) J Cell Biol 113:195–205

    Article  CAS  PubMed  Google Scholar 

  5. Marti T, Rosselet SJ, Titani K, Walsh KA (1987) Biochemistry 26:8099–8109

    CAS  PubMed  Google Scholar 

  6. Hoyer LW, Shainoff JR (1980) Blood 55:1056–1059

    CAS  PubMed  Google Scholar 

  7. Federici AB, Bader R, Pagani S, Colibretti ML, De Marco L, Mannucci PM (1989) Br J Haematol 73:93–99

    CAS  PubMed  Google Scholar 

  8. Schneppenheim R, Budde U, Oyen F, Angerhaus D, Aumann V, Drewke E, Hassenpflug W, Haberle J, Kentouche K, Kohne E, Kurnik K, Mueller-Wiefel D, Obser T, Santer R, Sykora K-W (2003) Blood 101:1845–1850

    Article  CAS  PubMed  Google Scholar 

  9. Kokame K, Matsumoto M, Soejima K, Yagi H, Ishizashi H, Funato M, Tamai H, Konno M, Kamide K, Kawano Y, Miyata T, Fujimura Y (2002) Proc Natl Acad Sci 99:11902–11907

    Article  CAS  PubMed  Google Scholar 

  10. Dent JA, Berkowitz SD, Ware J, Kasper CK, Ruggeri ZM (1990) Proc Natl Acad Sci 87:6306–6310

    CAS  PubMed  Google Scholar 

  11. Levy GG, Nichols WC, Lian EC, Foroud T, McClintick JN, McGee BM, Yang AY, Siemieniak DR, Stark KR, Gruppo R, Sarode R, Shurin SB, Chandrasekaran V, Stabler SP, Sabio H, Bouhassira EE, Upshaw Jr JD, Ginsburg D, Tsai HM (2001) Nature 413:488–494

    Article  CAS  PubMed  Google Scholar 

  12. Verweij CL, Quadt R, Briet E, Dubbeldam K, van Ommen GB, Pannekoek H (1988) J Clin Invest 81:1116–1121

    CAS  PubMed  Google Scholar 

  13. Lyons SE, Cooney KA, Bockenstedt P, Ginsburg D (1994) Blood 83:1551–1557

    CAS  PubMed  Google Scholar 

  14. Sadler JE (1994) Thromb Haemost 71:520–525

    CAS  PubMed  Google Scholar 

  15. Lyons SE, Bruck ME, Bowie EJ, Ginsburg D (1992) J Biol Chem 267:4424–4430

    CAS  PubMed  Google Scholar 

  16. Marti-Renom MA, Stuart AC, Fiser A, Sanchez R, Melo F, Sali A (2000) Annu Rev Biophys Biomol Struct 29:291–325

    Article  CAS  PubMed  Google Scholar 

  17. Jenkins PV, Pasi KJ, Perkins SJ (1998) Blood 91:2032–2044

    CAS  PubMed  Google Scholar 

  18. Altschul SF, Madden TL, Schaffer AA, Zhang J, Zhang Z, Miller W, Lipman DJ (1997) Nucleic Acids Res 25:3389–3402

    CAS  PubMed  Google Scholar 

  19. Shindyalov IN, Bourne PE (1998) Protein Eng 11:739–747

    Article  CAS  PubMed  Google Scholar 

  20. Smith TF, Waterman MS (1981) J Mol Biol 147:195–197

    CAS  PubMed  Google Scholar 

  21. Kelley LA, MacCallum RM, Sternberg MJ (2000) J Mol Biol 299:499–520

    Article  CAS  PubMed  Google Scholar 

  22. Fischer D (2000) World Sci 119–130

  23. Jones DT (1999) J Mol Biol 287:797–815

    Article  CAS  PubMed  Google Scholar 

  24. Needleman SB, Wunsch CD (1970) J Mol Biol 48:443–453

    CAS  PubMed  Google Scholar 

  25. MODELLER, version 6.0 (2001)http://www.salilab.org/modeller/modeller.html

  26. Rychlewski L, Jaroszewski L, Li W, Godzik A (2000) Protein Sci 9:232–241

    CAS  PubMed  Google Scholar 

  27. Bates P, Jackson RM, Sternberg MJ (1997) Proteins Suppl 1:59–67

    Article  Google Scholar 

  28. Bates P, Kelley LA, MacCallum RM, Sternberg MJ (2001) Proteins Suppl 5:39–46

    Article  Google Scholar 

  29. Karplus K, Barrett C, Hughey R (1998) Bioinformatics 14:846–856

    Article  CAS  PubMed  Google Scholar 

  30. Eddy SR (2001)http://hmmer.wustl.edu/

  31. Bateman A, Birney E, Cerruti L, Durbin R, Etwiller L, Eddy SR, Griffiths-Jones S, Howe KL, Marshall M, Sonnhammer ELL (2002) Nucleic Acids Res 30:276–280

    Article  CAS  PubMed  Google Scholar 

  32. Grubmueller H (1996)http://www.mpibpc.gwdg.de/abteilungen/071/solvate/docu.html

  33. Kale L, Skeel R, Bhandarkar M, Brunner R, Gursoy A, Krawetz N, Phillips J, Shinozaki A, Varadarajan K, Schulten K (1999) J Comput Phys 151:283–312

    Article  CAS  Google Scholar 

  34. MacKerell AD, Bashford D, Bellott M, Dunbrack RL, Evanseck JD, Field MJ, Fischer S, Gao J, Guo H, Ha S, Joseph-McCarthy D, Kuchnir L, Kuczera K, Lau FTK, Mattos C, Michnick S, Ngo T, Nguyen DT, Prodhom B, Reiher III WE, Roux B, Schlenkrich M, Smith JC, Stote R, Straub J, Watanabe M, Wiorkiewicz-Kuczera J, Yin D, Karplus M (1998) J Phys Chem B 102:3586–3616

    Article  CAS  Google Scholar 

  35. Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML (1983) J Chem Phys 79:926–935

    Article  CAS  Google Scholar 

  36. Ryckaert J-P, Ciccotti G, Berendsen HJC (1977) J Comput Phys 23:327–341

    CAS  Google Scholar 

  37. Darden T, York D, Pedersen L (1993) J Chem Phys 98:10089–10092

    Article  CAS  Google Scholar 

  38. Feller SE, Zhang YH, Pastor RW, Brooks BR (1995) J Chem Phys 103:4613–4621

    Article  CAS  Google Scholar 

  39. Tuckerman M, Berne BJ, Martyna GJ (1992) J Chem Phys 97:1990–2001

    Article  CAS  Google Scholar 

  40. Lee B, Richards FM (1971) J Mol Biol 55:379–389

    CAS  PubMed  Google Scholar 

  41. Kabsch W, Sander C (1983) Biopolymers 22:2577–2637

    CAS  PubMed  Google Scholar 

  42. Lee JO, Bankston L, Arnaout MA, Liddington R (1995) Structure 15:1333–1340

    Article  Google Scholar 

  43. Sauder JM, Arthur JW, Dunbrack RL (2000) Proteins 40:6–22

    Article  CAS  PubMed  Google Scholar 

  44. Jones DT (1999) J Mol Biol 292:195–202

    Article  CAS  PubMed  Google Scholar 

  45. Rost B, Sander C (1993) J Mol Biol 232:584–599

    Article  CAS  PubMed  Google Scholar 

  46. Cuff JA, Clamp ME, Siddiqui AS, Finlay M, Barton GJ (1998) Bioinformatics 14:892–893

    Article  CAS  PubMed  Google Scholar 

  47. Sippl MJ (1993) Proteins 17:355–362

    CAS  PubMed  Google Scholar 

  48. Honig B, Nicholls A (1995) Science 268:1144–1149

    CAS  PubMed  Google Scholar 

  49. Tramontano A, Leplae R, Morea V (2001) Proteins Suppl 5:22–38

    Article  Google Scholar 

  50. Edwards YJ, Perkins SJ (1995) FEBS Lett 358:283–286

    Article  CAS  PubMed  Google Scholar 

  51. Edwards YJ, Perkins SJ (1996) J Mol Biol 260:277–285

    Article  CAS  PubMed  Google Scholar 

  52. Lehninger AL, Nelson DL, Cox MM (1993) Principles of biochemistry. Worth Publishers, New York

  53. Lankhof H, Damas C, Schiphorst ME, Ijsseldijk MJW, Bracke M, Furlan M, de Groot PG, Sixma JJ, Vink T (1999) Thromb Haemost 81:976–983

    CAS  PubMed  Google Scholar 

  54. Kokame K, Matsumoto M, Fujimura Y, Miyata T (2004) Blood 103:607–612

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Z. Jia and the Department of Biochemistry, and A. Becke for providing access to computing resources. JJS acknowledges support from a Canadian Institute of Health Research doctoral research award. LAO acknowledges support from a Canadian Blood Services graduate fellowship. DL is the recipient of a Canada Research Chair in Molecular Hemostasis and a Career Investigator Award from the Heart and Stroke Foundation of Ontario. DFW acknowledges support from the Canada Research Chairs program. This study has been funded in part by grants from the Canadian Institutes of Health Research (MOP42467) and the Heart and Stroke Foundation of Ontario (T4421).

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Authors and Affiliations

  1. Department of Chemistry, Queen’s University, Kingston, Ontario, K7L 3N6, Canada

    Jeffrey J. Sutherland

  2. Department of Pathology, Queen’s University, Kingston, Ontario, K7L 3N6, Canada

    Lee A. O’Brien & David Lillicrap

  3. Departments of Medicine (Neurology) and Chemistry and School of Biomedical Engineering, Dalhousie University, Halifax, Nova Scotia, B3H 4J3, Canada

    Donald F. Weaver

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  1. Jeffrey J. Sutherland
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  2. Lee A. O’Brien
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  3. David Lillicrap
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  4. Donald F. Weaver
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Correspondence to Donald F. Weaver.

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Sutherland, J.J., O’Brien, L.A., Lillicrap, D. et al. Molecular modeling of the von Willebrand factor A2 Domain and the effects of associated type 2A von Willebrand disease mutations. J Mol Model 10, 259–270 (2004). https://doi.org/10.1007/s00894-004-0194-9

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  • DOI: https://doi.org/10.1007/s00894-004-0194-9

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