PrP(106-126) does not interact with membranes under physiological conditions.
Transmissible spongiform encephalopathies are neurodegenerative diseases characterized by the accumulation of an abnormal isoform of the prion protein PrP(Sc). Its fragment 106-126 has been reported to maintain most of the pathological features of PrP(Sc), and a role in neurodegeneration has been proposed based on the modulation of membrane properties and channel formation. The ability of PrP(Sc) to modulate membranes and/or form channels in membranes has not been clearly demonstrated; however, if these processes are important, peptide-membrane interactions would be a key feature in the toxicity of PrP(Sc). In this work, the interaction of PrP(106-126) with model membranes comprising typical lipid identities, as well as more specialized lipids such as phosphatidylserine and GM1 ganglioside, was examined using surface plasmon resonance and fluorescence methodologies. This comprehensive study examines different parameters relevant to characterization of peptide-membrane interactions, including membrane charge, viscosity, lipid composition, pH, and ionic strength. We report that PrP(106-126) has a low affinity for lipid membranes under physiological conditions without evidence of membrane disturbances. Membrane insertion and leakage occur only under conditions in which strong electrostatic interactions operate. These results support the hypothesis that the physiological prion protein PrP(C) mediates PrP(106-126) toxic effects in neuronal cells.
Henriques
Sónia Troeira
ST
Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal.
Pattenden
Leonard Keith
LK
Aguilar
Marie-Isabel
MI
Castanho
Miguel A R B
MA
D001665:Binding Sites; D008081:Liposomes / Q000737:chemistry*; D008563:Membrane Lipids / Q000737:chemistry*; D008567:Membranes, Artificial; D010446:Peptide Fragments / Q000737:chemistry*; D010743:Phospholipids / Q000737:chemistry*; D011328:Prions / Q000737:chemistry*; D011485:Protein Binding; D017434:Protein Structure, Tertiary
D008081:Liposomes; D008563:Membrane Lipids; D008567:Membranes, Artificial; D010446:Peptide Fragments; D010743:Phospholipids; D011328:Prions; C082632:prion protein (106-126)