title: Structural effects of PrP polymorphisms on intra- and interspecies prion transmission.
abstract: Understanding the molecular parameters governing prion propagation is crucial for controlling these lethal, proteinaceous, and infectious neurodegenerative diseases. To explore the effects of prion protein (PrP) sequence and structural variations on intra- and interspecies transmission, we integrated studies in deer, a species naturally susceptible to chronic wasting disease (CWD), a burgeoning, contagious epidemic of uncertain origin and zoonotic potential, with structural and transgenic (Tg) mouse modeling and cell-free prion amplification. CWD properties were faithfully maintained in deer following passage through Tg mice expressing cognate PrP, and the influences of naturally occurring PrP polymorphisms on CWD susceptibility were accurately reproduced in Tg mice or cell-free systems. Although Tg mice also recapitulated susceptibility of deer to sheep prions, polymorphisms that provided protection against CWD had distinct and varied influences. Whereas substitutions at residues 95 and 96 in the unstructured region affected CWD propagation, their protective effects were overridden during replication of sheep prions in Tg mice and, in the case of residue 96, deer. The inhibitory effects on sheep prions of glutamate at residue 226 in elk PrP, compared with glutamine in deer PrP, and the protective effects of the phenylalanine for serine substitution at the adjacent residue 225, coincided with structural rearrangements in the globular domain affecting interaction between α-helix 3 and the loop between β2 and α-helix 2. These structure-function analyses are consistent with previous structural investigations and confirm a role for plasticity of this tertiary structural epitope in the control of PrP conversion and strain propagation.
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, KY 40506;
authors.forename: Rachel
authors.initials: R
authors.lastname: Angers
authors.affiliation: Prion Research Center and Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523;
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Christiansen
authors.affiliation: Prion Research Center and Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523;
authors.forename: Amy V
authors.initials: AV
authors.lastname: Nalls
authors.affiliation: Prion Research Center and Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523;
authors.forename: Hae-Eun
authors.initials: HE
authors.lastname: Kang
authors.affiliation: The Roslin Institute, University of Edinburgh, Midlothian EH25 9RG, United Kingdom; and.
authors.forename: Nora
authors.initials: N
authors.lastname: Hunter
authors.affiliation: Prion Research Center and Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523;
authors.forename: Edward
authors.initials: E
authors.lastname: Hoover
authors.affiliation: Prion Research Center and Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523;
authors.forename: Candace K
authors.initials: CK
authors.lastname: Mathiason
authors.affiliation: Center for Computational Sciences, University of Kentucky, Lexington, KY 40506.
authors.forename: Michael
authors.initials: M
authors.lastname: Sheetz
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, KY 40506;Prion Research Center and Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523; glenn.telling@colostate.edu.
authors.forename: Glenn C
authors.initials: GC
authors.lastname: Telling
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D003670:Deer; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D011110:Polymorphism, Genetic; D018620:PrPSc Proteins / Q000235:genetics* / Q000378:metabolism; D017433:Protein Structure, Secondary; D012756:Sheep; D012757:Sheep Diseases / Q000235:genetics / Q000378:metabolism; D034081:Wasting Disease, Chronic / Q000235:genetics / Q000378:metabolism
chemical_list: D018620:PrPSc Proteins
keywords: prion replication; protective polymorphisms; protein structure; structural plasticity