Binding of prion proteins to lipid membranes

A key molecular event in prion diseases is the conversion of the normal cellular form of the prion protein (PrP C) to an aberrant form known as the scrapie isoform, PrP Sc. Under normal physiological conditions PrP C is attached to the outer leaflet of the plasma membrane via a GPI-anchor. It has been proposed that a direct interaction between PrP and lipid membranes could be involved in the conversion of PrP C to its disease-associated corrupted conformation, PrP Sc. Recombinant PrP can be refolded into an α-helical structure, designated α-PrP isoform, or into β-sheet-rich states, designated β-PrP isoform. The current study investigates the binding of recombinant PrP isoforms to model lipid membranes using surface plasmon resonance spectroscopy. The binding of α- and β-PrP to negatively charged lipid membranes of POPG, zwitterionic membranes of DPPC, and model raft membranes composed of DPPC, cholesterol, and sphingomyelin is compared at pH 7 and 5, to simulate the environment at the plasma membrane and within endosomes, respectively. It is found that PrP binds strongly to lipid membranes. The strength of the association of PrP with lipid membranes depends on the protein conformation and pH, and involves both hydrophobic and electrostatic lipid–protein interactions. Competition binding measurements established that the binding of α-PrP to lipid membranes follows a decreasing order of affinity to POPG > DPPC > rafts.