Get access
Advertisement

Structural facets of disease-linked human prion protein mutants: A molecular dynamic study

Authors

  • Giulia Rossetti,

    1. Statistical and Biological Physics Sector, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136 Trieste, Italy
    2. CNR-INFM-Democritos National Simulation Center, Beirut 2-4, Trieste, Italy
    3. Italian Institute of Technology—SISSA Unit, Via Beirut 2-4, Trieste, Italy
    4. German Research School for Simulation Science, FZ-Jülich and RWTH Aachen, Germany
    Search for more papers by this author
  • Gabriele Giachin,

    1. Laboratory of Prion Biology, Neurobiology Sector, International School for Advanced Studies (SISSA) via Bonomea 265, 34136 Trieste, Italy
    Search for more papers by this author
  • Giuseppe Legname,

    1. Italian Institute of Technology—SISSA Unit, Via Beirut 2-4, Trieste, Italy
    2. Laboratory of Prion Biology, Neurobiology Sector, International School for Advanced Studies (SISSA) via Bonomea 265, 34136 Trieste, Italy
    3. ELETTRA Laboratory, Sincrotrone Trieste S.C.p.A., I-34149 Basovizza, Trieste, Italy
    Search for more papers by this author
  • Paolo Carloni

    Corresponding author
    1. Statistical and Biological Physics Sector, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136 Trieste, Italy
    2. CNR-INFM-Democritos National Simulation Center, Beirut 2-4, Trieste, Italy
    3. Italian Institute of Technology—SISSA Unit, Via Beirut 2-4, Trieste, Italy
    4. German Research School for Simulation Science, FZ-Jülich and RWTH Aachen, Germany
    • Statistical and Biological Physics Sector, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136 Trieste, Italy
    Search for more papers by this author

Abstract

Prion propagation in transmissible spongiform encephalopathies involves the conversion of the cellular prion protein, PrPC, into the pathogenic conformer PrPSc. Human familial forms of the disease are linked to specific mutations in the PrP gene, PRNP, and include Gerstmann-Sträussler-Scheinker syndrome (GSS), familial Creutzfeldt-Jakob disease (fCJD), and fatal familial insomnia. To gain insights into the molecular basis of these disorders, we performed 200 ns of classical molecular dynamic simulations in aqueous solution on wild type (WT) human PrP (HuPrP), and on three HuPrP variants located in the globular HuPrP domain: two pathological mutations, HuPrP(Q212P) and HuPrP(E200K), linked to GSS and to fCJD respectively, and one protective polymorphism, HuPrP(E219K) (total time-scale simulated 800 ns). A comparison between the predicted structural determinants of WT HuPrP and HuPrP(E200K) with their NMR structures established the accuracy of the methods used. Strikingly, the analyzed disease-linked variants produced their major effect on the α23 region and the β22 loop, regardless of the mutation position. The conformational change of the latter might affect the interactions with cellular partners in the fibrillation process. The protocol proposed here represents a powerful approach for reproducing the structural effects of genetic mutations located in the globular domain of HuPrP, such as the GSS-related HuPrP(Q212P) and the protective polymorphism HuPrP(E219K). Proteins 2010. © 2010 Wiley-Liss, Inc.

Get access to the full text of this article

Ancillary