title: Disruption of the X-loop turn of the prion protein linked to scrapie resistance.
abstract: The prion diseases are a class of neurodegenerative diseases caused by the misfolding and aggregation of the prion protein (PrP(C)) into toxic and infectious oligomers (PrP(Sc)). These oligomers are critical to understanding and combating these diseases. Differences in the sequence of PrP affect disease susceptibility, likely by shifting the tolerance of the protein for adaptation to PrP(Sc) conformations and/or the recognition event between PrP(Sc) and PrP(C) prior to conversion of the PrP(C). We selected two sets of PrP(Sc)-resistant mutant sequences for solvated atomistic molecular dynamics simulation to investigate the structural basis of resistance. The first group involved mutation in the X-loop (residues 164-171) resulting from selective breeding of sheep. The second group included eight mutants in mice identified by random mutagenesis targeting helix C followed by screening in cell cultures. Multiple simulations were performed of 14 different mutant and control constructs under different pH conditions for a total of 3.6 μs of simulation time. The X-loop formed a stable turn at neutral pH in wild-type PrP from both species. PrP(Sc)-resistant mutations disrupted this turn even though only one of the mutants is in the X-loop. The X-loop is compact and buried in our previously described spiral models of PrP(Sc)-like oligomers. On the basis of the findings presented here and in the context of the spiral oligomer model, we propose that expansion of the X-loop disrupts protofibril packing, providing a structural basis for resistance.
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA 98195-5013, USA.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Scouras
authors.forename: Valerie
authors.initials: V
authors.lastname: Daggett
mesh_terms: D000818:Animals; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D018620:PrPSc Proteins / Q000737:chemistry* / Q000235:genetics; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D012608:Scrapie / Q000235:genetics*; D012756:Sheep / Q000235:genetics / Q000276:immunology
chemical_list: D018620:PrPSc Proteins