Anionic Lipid Interaction Induces Prion Protein Conformational Change

Abstract

The conversion of the prion protein (PrP) to the pathogenic PrPScconformation plays a central role in prion disease. However, the precise mechanism underlying this process remains unclear. Here, we report the conformational conversion of PrP upon interaction with anionic lipids. After the discontinuous iodixanol density gradient centrifugation, we found strong binding between PrP and negatively charged phospholipids, involving both electrostatic and hydrophobic interactions. Under physiologically relevant conditions, interactions with lipid were sufficient to convert full-length, α helices rich recombinant mouse PrP to a conformation similar to PrPSc, with increased β sheet content and a PrPSc-like proteinase K (PK)-resistant pattern. Conversion is greatly influenced by lipid headgroup structures and lipid vesicle compositions. When lipid vesicles are disrupted by detergent, aggregation is necessary to maintain the PK resistant conformation. Our results imply that the strong lipid-PrP interaction is sufficient to overcome the energy barrier between the two conformational states and support the notion that lipid membrane may play a role in PrP conformational change.