title: Failure of prion protein oxidative folding guides the formation of toxic transmembrane forms.
abstract: The mechanism by which pathogenic mutations in the globular domain of the cellular prion protein (PrP(C)) increase the likelihood of misfolding and predispose to diseases is not yet known. Differences in the evidences provided by structural and metabolic studies of these mutants suggest that in vivo folding could be playing an essential role in their pathogenesis. To address this role, here we use the single or combined M206S and M213S artificial mutants causing labile folds and express them in cells. We find that these mutants are highly toxic, fold as transmembrane PrP, and lack the intramolecular disulfide bond. When the mutations are placed in a chain with impeded transmembrane PrP formation, toxicity is rescued. These results suggest that oxidative folding impairment, as on aging, can be fundamental for the genesis of intracellular neurotoxic intermediates key in prion neurodegenerations.
authors.affiliation: Instituto Química-Física Rocasolano, Consejo Superior de Investigaciones Científicas, Serrano 119, 28006 Madrid, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Lisa
authors.forename: Beatriz
authors.initials: B
authors.lastname: Domingo
authors.forename: Javier
authors.initials: J
authors.lastname: Martínez
authors.forename: Sabine
authors.initials: S
authors.lastname: Gilch
authors.forename: Juan F
authors.initials: JF
authors.lastname: Llopis
authors.forename: Hermann M
authors.initials: HM
authors.lastname: Schätzl
authors.forename: María
authors.initials: M
authors.lastname: Gasset
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D002470:Cell Survival; D003553:Cystine / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D051379:Mice; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D011328:Prions / Q000235:genetics / Q000378:metabolism*; D017510:Protein Folding; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D021381:Protein Transport
chemical_list: C110396:(ctm)PrP; D050505:Mutant Proteins; D011328:Prions; D003553:Cystine