PrP(106-126) does not interact with membranes under physiological conditions
Sónia Troeira Henriques 1, Leonard Keith Pattenden 2, Marie Isabel Aguilar 2 and Miguel A.R.B. Castanho 3*
1 Faculdade Medicina Univ. Lisboa
2 Monash University
3 Faculdade de Medicina Univ Lisboa
* To whom correspondence should be addressed. E-mail: macastanho{at}fm.ul.pt.
Submitted on February 14, 2008
Revised on April 3, 2008
Accepted on 18 April 2008
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Abstract |
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Transmissible spongiform encephalopathies are neurodegenerative diseases with characteristic accumulation of an abnormal isoform of the prion protein, PrPSc. Its fragment 106-126 was reported to maintain most of the pathological features of PrPSc and a role in neurodegeneration was proposed based on the modulation of membrane properties and channel formation. While the ability of PrPSc to modulate membranes and/or form channels in membranes has not been clearly demonstrated, if these processes are important, peptide-membrane interactions would be a key feature to the toxicity of PrPSc. In the present work, the interaction of PrP(106-126) with model membranes comprising typical lipid identities as well as more specialised lipids such as phosphatidylserine and GM1 ganglioside, was examined using surface plasmon resonance and fluorescence methodologies. This comprehensive study examines different parameters relevant to characterisation 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 for membrane disturbances. Membrane insertion and leakage only occurs under conditions where strong electrostatic interactions operate. These results support the hypothesis that the physiological prion protein, PrPC, mediates PrP(106-126) toxic effects in neuronal cells.
Key Words:
Fluorescence methodologies, Model membranes, Pore formation, Prion Disease, Surface Plasmon Resonance
