NR AOUP
AU Kazlauskaite,J.; Venien-Bryan,C.; Pinheiro,T.J.T.
TI Aggregation and Fibriilization of Prion Proteins
QU International Conference - Prion diseases: from basic research to intervention concepts - TSE-Forum, 08.10.-10.10.2003, Gasteig, München - Poster session - BR-99
PT Konferenz-Poster
AB Prion diseases are associated with a major refolding event of the normal cellular prion protein, PrPc, where the predominantly a-helical and random coil structure of PrPc is converted into a b-sheet-rich aggregated form, PrPsc. Under normal physiological conditions PrPc is attached to the outer leaflet of the plasma membrane via a GPI-anchor, and it is plausible that an interaction between PrP and lipid membranes could be involved in the conversion of PrPc into PrPsc. Recombinant PrP can be refolded into a a-helical structure, designated a-PrP isoform, or into b-sheet-rich states, termed b-PrP isoform. Here, we present the different binding properties of a- and b-PrP to model lipid membranes, the protein structural changes induced upon binding to lipid membranes, the destabilising effect of PrP to the membrane and resulting aggregation and fibrillization of PrP. The key findings, resulting from a combination of fluorescence, CD, FTIR and EM studies, are that: a) binding of a- and b-PrP to negatively charged lipid membranes results in increased b-sheet structure in PrP, which destabilises the lipid membranes and leads to amorphous aggregation of PrP; b) binding of a-PrP to raft membranes increases a-helical structure, which does not destabilise the lipid membrane and does not lead to PrP aggregation; and c) binding of b-PrP to rafts induces unfolding of PrP, which does not destabilise the lipid membrane but leads to fibrillization of PrP. The mechanism of fibrillization of PrP and underlying protein structural changes are further examined in solution and in membranes using FTIR and EM.
AD Jurate Kazlauskaite, Teresa J.T. Pinheiro, Warwick University, UK; Catherine Venien-Bryan, Oxford University, UK
SP englisch
PO Deutschland