Keywords: Disulfide Bond, Energy Landscape, Intermediate State, N-Terminal Domain, Prion-Susceptible Species, Octapeptide, Prion Protein, Article, Dielectric Constant, Enthalpy, Human, Nonhuman, Protein Analysis, Protein Folding, Protein Function, Protein Stability, Protein Structure, Simulation, Animals, Calorimetry, Differential Scanning, Disulfides Chemistry Metabolism, Molecular Dynamics Simulation, Mutation, Prions Chemistry Genetics Metabolism, Protein Isoforms, Protein Processing, Post-Translational, Spectrometry, Fluorescence,
Affiliations: *** IBB - CNR ***
Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati, Via Bonomea 265Trieste, Italy
Italian Institute of Technology, Scuola Internazionale Superiore di Studi Avanzati Unit, Via Bonomea 265Trieste, Italy
Department of Physics, Scuola Internazionale Superiore di Studi AvanzatiTrieste, Italy
National Research Council, Institute of Biostructures and Bioimaging, Viale Andrea Doria 6Catania, Italy
Elettra - Sincrotrone Trieste S.C.p.A., AREA Science ParkBasovizza Trieste, Italy
European Center for the Sustainable Impact of Nanotechnology, Veneto Nanotech S.C.p.A.Rovigo, Italy
Laboratory of Biochemistry, Institut Químic de Sarrià, Universitat Ramon Llull, Via Augusta 390Barcelona, Spain
References: Not available.
Structural determinants in prion protein folding and stability
Prions are responsible for a heterogeneous group of fatal neurodegenerative diseases, involving post-translational modifications of the cellular prion protein. Epidemiological studies on Creutzfeldt-Jakob disease, a prototype prion disorder, show a majority of cases being sporadic, while the remaining occurrences are either genetic or iatrogenic. The molecular mechanisms by which PrPC is converted into its pathological isoform have not yet been established. While point mutations and seeds trigger the protein to cross the energy barriers, thus causing genetic and infectious transmissible spongiform encephalopathies, respectively, the mechanism responsible for sporadic forms remains unclear. Since prion diseases are protein-misfolding disorders, we investigated prion protein folding and stability as functions of different milieus. Using spectroscopic techniques and atomistic simulations, we dissected the contribution of major structural determinants, also defining the energy landscape of prion protein. In particular, we elucidated (i) the essential role of the octapeptide region in prion protein folding and stability, (ii) the presence of a very enthalpically stable intermediate in prion-susceptible species, and (iii) the role of the disulfide bridge in prion protein folding.
Structural determinants in prion protein folding and stability
No results.
Structural determinants in prion protein folding and stability