ɑ-Helices in Prion Protein Monomer and Dimers Drive the Interaction with the Cell Membrane Interface

Abstract

Introduction Prions propagate through the conversion of the cellular form of the protein, PrPC, to the infectious form, PrPSc (Prusiner 1991; Büeler et al. 1993; Caugheys and Raymond 1991). Prions can replicate without nucleic acids and lead to transmissible spongiform encephalopathies (TSE), a form of fatal neurodegenerative diseases in mammals (Prusiner et al. 1998). Cellular PrPC is attached to the outer leaflet of the membrane with an extracellular glycoprotein glycosylphosphatidylinositol (GPI) anchor (Stahl et al. 1987). The physiological role of prion proteins remains unclear, however the conformation of PrPC has been analyzed using structural biophysics techniques. The N-terminus of the cellular prion protein is flexible, while the C-terminus has a globular domain and includes three ɑhelices and a β-sheet. The misfolded form, PrPSc, is rich in ɑ-sheet but an atomic level structure has not been resolved yet (Pan et al. 1993). Though the mechanism of prion conversion and propagation is not well understood, polymerization of prion proteins suggests that a misfolded seed triggers the misfolding of PrPC.