title: Dominant-negative effects in prion diseases: insights from molecular dynamics simulations on mouse prion protein chimeras.
abstract: Mutations in the prion protein (PrP) can cause spontaneous prion diseases in humans (Hu) and animals. In transgenic mice, mutations can determine the susceptibility to the infection of different prion strains. Some of these mutations also show a dominant-negative effect, thus halting the replication process by which wild type mouse (Mo) PrP is converted into Mo scrapie. Using all-atom molecular dynamics (MD) simulations, here we studied the structure of HuPrP, MoPrP, 10 Hu/MoPrP chimeras, and 1 Mo/sheepPrP chimera in explicit solvent. Overall, ∼2 μs of MD were collected. Our findings suggest that the interactions between α1 helix and N-terminal of α3 helix are critical in prion propagation, whereas the β2-α2 loop conformation plays a role in the dominant-negative effect. An animated Interactive 3D Complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:4 .
authors.affiliation: Department of Physics, Scuola Internazionale Superiore di Studi Avanzati-SISSA, Via Bonomea 265, 34136 Trieste, Italy.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Cong
authors.forename: Salvatore
authors.initials: S
authors.lastname: Bongarzone
authors.forename: Gabriele
authors.initials: G
authors.lastname: Giachin
authors.forename: Giulia
authors.initials: G
authors.lastname: Rossetti
authors.forename: Paolo
authors.initials: P
authors.lastname: Carloni
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Legname
mesh_terms: D000818:Animals; D005799:Genes, Dominant; D051379:Mice; D056004:Molecular Dynamics Simulation; D017096:Prion Diseases / Q000235:genetics; D000072002:Prion Proteins; D011328:Prions / Q000737:chemistry* / Q000235:genetics; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization
chemical_list: D000072002:Prion Proteins; D011328:Prions; C512657:Prnp protein, mouse