title: Contribution of two conserved glycine residues to fibrillogenesis of the 106-126 prion protein fragment. Evidence that a soluble variant of the 106-126 peptide is neurotoxic.
abstract: The fibrillogenic peptide corresponding to the residues 106-126 of the prion protein sequence (PrP 106-126) is largely used to explore the neurotoxic mechanisms underlying the prion disease. However, whether the neuronal toxicity of PrP 106-126 is caused by a soluble or fibrillar form of this peptide is still unknown. The aim of this study was to correlate the structural state of this peptide with its neurotoxicity. Here we show that the two conserved Gly114 and Gly119 residues, in force of their intrinsic flexibility, prevent the peptide assuming a structured conformation, favouring its aggregation in amyloid fibrils. The substitution of both Gly114 and Gly119 with alanine residues (PrP 106-126 AA mutated peptide) reduces the flexibility of this prion fragment and results in a soluble, beta-structured peptide. Moreover, PrP 106-126 AA fragment was highly toxic when incubated with neuroblastoma cells, likely behaving as a neurotoxic protofibrillar intermediate of the wild-type PrP 106-126. These data further confirm that the fibrillar aggregation is not necessary for the induction of the toxic effects of PrP 106-126.
authors.affiliation: Department Oncology, Biology and Genetics, Sect. Pharmacology, University of Genova, Italy.
authors.forename: Tullio
authors.initials: T
authors.lastname: Florio
authors.forename: Domenico
authors.initials: D
authors.lastname: Paludi
authors.forename: Valentina
authors.initials: V
authors.lastname: Villa
authors.forename: Daniela Rossi
authors.initials: DR
authors.lastname: Principe
authors.forename: Alessandro
authors.initials: A
authors.lastname: Corsaro
authors.forename: Enrico
authors.initials: E
authors.lastname: Millo
authors.forename: Gianluca
authors.initials: G
authors.lastname: Damonte
authors.forename: Cristina
authors.initials: C
authors.lastname: D'Arrigo
authors.forename: Claudio
authors.initials: C
authors.lastname: Russo
authors.forename: Gennaro
authors.initials: G
authors.lastname: Schettini
authors.forename: Antonio
authors.initials: A
authors.lastname: Aceto
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002942:Circular Dichroism; D017124:Conserved Sequence; D005998:Glycine / Q000737:chemistry*; D006801:Humans; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D009447:Neuroblastoma / Q000188:drug therapy; D009498:Neurotoxins / Q000737:chemistry / Q000633:toxicity; D010446:Peptide Fragments / Q000737:chemistry* / Q000633:toxicity*; D017096:Prion Diseases / Q000209:etiology; D011328:Prions / Q000737:chemistry* / Q000633:toxicity*; D017433:Protein Structure, Secondary / Q000502:physiology; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D046911:Macromolecular Substances; D009498:Neurotoxins; D010446:Peptide Fragments; D011328:Prions; C082632:prion protein (106-126); D005998:Glycine