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Prion Diseases pp 251-263 | Cite as

The prion protein globular domain and disease-related mutants studied by molecular dynamics simulations

  • M. Billeter
  • K. Wüthrich
Chapter
Part of the Archives of Virology. Supplementa book series (ARCHIVES SUPPL, volume 16)

Summary

In humans, familial forms of transmissible spongiform enceph-alopathies (TSE; “prion diseases”) have been shown to segregate with the exchange of individual amino acids in the prion protein (PrP) sequence. We used the NMR structure of the globular domain of mouse PrP in the cellular form (PrPC) as a starting point for investigations by long-time molecular dynamics (MD) simulations at ambient temperature of likely impacts of such mutations on the PrPC structure, making use of the fact that species-related amino acid replacements between mouse PrP and human PrP are spatially well separated from the disease-related mutations in human PrP. In the MD simulations these amino acid substitutions were found to have a variety of different effects on the protein structure, with some species showing altered packing of regular secondary structure elements, while other mutants showed no or only strictly localized changes of the structure near the variant amino acid. The fact that some of the disease-related amino acid exchanges cause no measurable change of the PrPC structure indicates that their influence on the conformational transition to the scrapie form of PrP may be due to modified intermolecular interactions during the aggregation process.

Keywords

Molecular Dynamic Simulation Prion Protein Prion Disease Amino Acid Replacement Fatal Familial Insomnia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Aguzzi A, Weissmann C (1997) Prion research: the next frontiers. Nature 389; 795–798PubMedCrossRefGoogle Scholar
  2. 2.
    Berendsen HJC, Postma JPM, van Gunsteren WF, DiNola A, Haak JR (1984) Molecular dynamics with coupling to an external bath. J Chem Phys 81; 3684–3690CrossRefGoogle Scholar
  3. 3.
    Billeter M, Riek R, Wider G, Hornemann S, Glockshuber R, Wüthrich K (1997) Prion protein NMR structure and species barrier for prion diseases, Proc Natl Acad Sci USA 94: 7281–7285PubMedCrossRefGoogle Scholar
  4. 4.
    Cohen FE, Pan KM, Huang ZW, Baldwin M, Fletterick RJ, Prµsiner SB (1994) Structural clues to prion replication, Science 264: 530–531PubMedCrossRefGoogle Scholar
  5. 5.
    Cornell WD, Cieplak P, Bayly CI, Gould IR, Merz Jr. KM, Ferguson DM, Spellmeyer DC, Fox T, Caldwell JW, Kollman PA (1995) A second generation force field for the simulation of proteins and nucleic acids. J Am Chem Soc 117: 5179–5197CrossRefGoogle Scholar
  6. 6.
    Donne DG, Viles JH, Groth D, Mehlhorn I, James TL, Cohen FE, Prusiner SB, Wright PE, Dyson HJ (1997) Structure of the recombinant full-length hamster prion protein PrP(29–231): the N-terminus is highly flexible. Proc Natl Acad Sci USA 94: 13452–13457PubMedCrossRefGoogle Scholar
  7. 7.
    Goldfarb LG, Petersen RB, Tabaton M, Brown P, LeBlanc AC, Montagna P, Cortelli P, Julien J, Vital C, Pendelbury WW, Haltia M, Wills PR, Hauw JJ, McKeever PE, Monari L, Schrank B, Swergold GD, Autilio-Gembetti L, Gajdusek DC, Lugaresi E, Gambetti P (1992) Fatal familial insomnia and familial Creutzfeldt-Jakob disease: disease phenotype determined by DNA polymorphism. Science 258: 806–808PubMedCrossRefGoogle Scholar
  8. 8.
    Harrison PM, Bamborough P, Daggett V, Prusiner SB, Cohen FE (1997) The prion folding problem. Curr Opin Struct Biol 7: 53–59PubMedCrossRefGoogle Scholar
  9. 9.
    James TL, Liu H, Ulyanov NB, Farr-Jones S, Zhang H, Donne DG, Kaneko K, Groth D, Mehlhorn I, Prusiner SB, Cohen FE (1997) Solution structure of a 142-residue recombinant prion protein corresponding to the infectious fragment of the scrapie isoform. Proc Natl Acad Sci USA 94: 10086–10091PubMedCrossRefGoogle Scholar
  10. 10.
    Jorgensen WJ, Chandrasekhar J, Madura JD, Impey RW, Klein ML (1983) Comparison of simple potential functions for simulating liquid water. J Chem Phys 79: 926–935CrossRefGoogle Scholar
  11. 11.
    Koradi R, Billeter M, Wüthrich K (1996) MOLMOL: A program for display and analysis of macromolecular structures. J Mol Graph 14: 51–55PubMedCrossRefGoogle Scholar
  12. 12.
    Liemann S, Glockshuber R (1999) Influence of amino acid substitutions related to inherited human prion diseases on the thermodynamic stability of the cellular prion protein. Biochemistry, 38: 3258–3267PubMedCrossRefGoogle Scholar
  13. 13.
    Luginbühl P, Güntert P, Billeter M, Wüthrich K (1996) The new program OPAL for molecular dynamics simulations and energy refinements of biological macro-molecules. J Biomol NMR 8: 136–146PubMedCrossRefGoogle Scholar
  14. 14.
    Prusiner SB (1997) Prion diseases and BSE crisis. Science 278: 245–251PubMedCrossRefGoogle Scholar
  15. 15.
    Prusiner SB (1998) Prions. Proc Natl Acad Sci USA 95: 13363–13383PubMedCrossRefGoogle Scholar
  16. 16.
    Riek R, Hornemann S, Wider G, Billeter M, Glockshuber R, Wüthrich K (1996) NMR structure of the mouse prion protein domain PrP(121–231). Nature 382: 180–182PubMedCrossRefGoogle Scholar
  17. 17.
    Riek R, Hornemann S, Wider G, Glockshuber R, Wüthrich K (1997) NMR characterization of the full length recombinant murine prion protein, mPrP-(23–231). FEBS Lett 413: 282–288PubMedCrossRefGoogle Scholar
  18. 18.
    Riek R, Wider G, Billeter M, Hornemann S, Glockshuber R, Wüthrich K (1998) Prion protein NMR structure and familial human transmissible spongiform encephalopathies. Proc Natl Acad Sci USA 95: 11667–11672PubMedCrossRefGoogle Scholar
  19. 19.
    Ryckaert J, Ciccotti G, Berendsen HCJ (1977) Numerical integration of the Cartesian equations of a system with constraints: molecular dynamics of n-alkanes. J Comput Phys 23: 327–341CrossRefGoogle Scholar
  20. 20.
    Schätzl HM, DaCosta M, Taylor L, Cohen FE, Prusiner SB (1995) Prion protein gene variation among primates. J Mol Biol 245: 362–374PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2000

Authors and Affiliations

  • M. Billeter
    • 1
  • K. Wüthrich
    • 2
  1. 1.Biochemistry and Biophysics, Lundberg LaboratoryGöteborg UniversityGöteborgSweden
  2. 2.Institut für Molekularbiologie und Biophysik, EidgenössischeTechnische HochschuleZürichSwitzerland

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