title: Structural determinants in prion protein folding and stability.
abstract: 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 PrP(C) 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.
authors.affiliation: Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati, Via Bonomea 265, I-34136 Trieste, Italy; Italian Institute of Technology, Scuola Internazionale Superiore di Studi Avanzati Unit, Via Bonomea 265, I-34136 Trieste, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Benetti
authors.affiliation: Department of Physics, Scuola Internazionale Superiore di Studi Avanzati, I-34136 Trieste, Italy.
authors.forename: Xevi
authors.initials: X
authors.lastname: Biarnés
authors.affiliation: National Research Council, Institute of Biostructures and Bioimaging, Viale Andrea Doria 6, I-95125 Catania, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Attanasio
authors.affiliation: Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati, Via Bonomea 265, I-34136 Trieste, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Giachin
authors.affiliation: National Research Council, Institute of Biostructures and Bioimaging, Viale Andrea Doria 6, I-95125 Catania, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Rizzarelli
authors.affiliation: Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati, Via Bonomea 265, I-34136 Trieste, Italy; Italian Institute of Technology, Scuola Internazionale Superiore di Studi Avanzati Unit, Via Bonomea 265, I-34136 Trieste, Italy; Elettra - Sincrotrone Trieste S.C.p.A., AREA Science Park, I-34149 Basovizza Trieste, Italy. Electronic address: legname@sissa.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Legname
mesh_terms: D000818:Animals; D002152:Calorimetry, Differential Scanning; D004220:Disulfides / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D051379:Mice; D056004:Molecular Dynamics Simulation; D009154:Mutation; D011328:Prions / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017510:Protein Folding; D020033:Protein Isoforms; D011499:Protein Processing, Post-Translational; D013050:Spectrometry, Fluorescence
chemical_list: D004220:Disulfides; D011328:Prions; D020033:Protein Isoforms
keywords: N-terminal domain; disulfide bond; energy landscape; intermediate state; prion-susceptible species