Misfolding and aggregation of cellular
prion protein (PrPc) is a major molecular process involved in the pathogenesis of
prion diseases. Here, we studied the aggregation properties of a
prion fragment peptide PrP(106-128). The results show that the
peptide aggregates in a concentration-dependent manner in an aqueous
solution and that the aggregation is sensitive to pH and the preformed
amyloid seeds. Furthermore, we show that the zwitterionic POPC
liposomes moderately inhibit the aggregation of PrP(106-128), whereas POPC/
cholesterol (8:2) vesicles facilitate
peptide aggregation likely due to the increase of the
lipid packing order and membrane rigidity in the presence of
cholesterol. In addition, anionic
lipid vesicles of POPG and POPG/
cholesterol above a certain concentration accelerate the aggregation of the
peptide remarkably. The strong electrostatic interactions between the N-terminal region of the
peptide and POPG may constrain the conformational plasticity of the
peptide, preventing insertion of the
peptide into the inner side of the membrane and thus promoting fibrillation on the membrane surface. The results suggest that the charge properties of the membrane, the composition of the
liposomes, and the rigidity of
lipid packing are critical in determining
peptide adsorption on the membrane surface and the efficiency of the membrane in catalyzing
peptide oligomeric nucleation and
amyloid formation. The
peptide could be used as an improved model molecule to investigate the mechanistic role of the crucial regions of PrP in aggregation in a membrane-rich environment and to screen effective inhibitors to block key interactions between these regions and membranes for preventing PrP aggregation.