title: The toxicity of prion protein fragment PrP(106-126) is not mediated by membrane permeabilization as shown by a M112W substitution.
abstract: Prion diseases result from a post-translational modification of the physiological prion protein (PrP(C)) into a scrapie isoform (PrP(Sc)). The PrP(106-126) fragment is conserved among various abnormal variants and shows PrP(Sc) pathogenic properties. It has been proposed that the PrP(106-126) fragment may exhibit its toxic effects through membrane pore formation. Our previous studies showed that PrP(106-126) does not interact with membranes under physiological conditions. In the present study, PrP(106-126) affinity for membranes was increased by modifying PrP(106-126) with a M112W substitution, and pore formation was further evaluated. However, while the peptide exhibited an increased local concentration in the membrane, this did not lead to the induction of membrane permeabilization, as verified by fluorescence methodologies and surface plasmon resonance. These results further support the idea that PrP(106-126) toxicity is not a consequence of peptide-membrane interaction and pore formation.
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Av. Egas Moniz, Edificio Egas Moniz, 1649-028 Lisboa, Portugal.
authors.forename: Sónia Troeira
authors.initials: ST
authors.lastname: Henriques
authors.forename: Leonard Keith
authors.initials: LK
authors.lastname: Pattenden
authors.forename: Marie-Isabel
authors.initials: MI
authors.lastname: Aguilar
authors.forename: Miguel A R B
authors.initials: MA
authors.lastname: Castanho
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002462:Cell Membrane / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D008564:Membrane Potentials; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry* / Q000633:toxicity*; D010539:Permeability; D018621:PrPC Proteins / Q000378:metabolism / Q000633:toxicity*; D011328:Prions / Q000737:chemistry* / Q000633:toxicity; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D055672:Static Electricity; D013816:Thermodynamics; D014364:Tryptophan / Q000378:metabolism; D014867:Water / Q000737:chemistry
chemical_list: D008051:Lipid Bilayers; D010446:Peptide Fragments; D018621:PrPC Proteins; D011328:Prions; C082632:prion protein (106-126); D014867:Water; D014364:Tryptophan