Unfold to refold: Tracking the initial steps of PrPc unfolding in the context of PrPsc propagation

Abstract

The structural elucidation of PrPSc, the infectious and misfolded conformer of the cellular prion protein (PrPC), was long anticipated to provide definitive insight into the enigmatic process of prion propagation. It was widely assumed that determining the atomic arrangement of PrPSc would directly unveil how PrPC converts into its pathogenic counterpart. Contrary to these expectations, PrPSc revealed itself as a relatively “simple” amyloid structure composed of repeating β-sheet motifs devoid of unique features beyond what is typically found in other amyloid fibrils. This finding suggested that PrPSc primarily serves as a passive structural template that stabilizes partially unfolded states of incoming PrPC monomers by sequestering them into a fibrillar conformation. This revelation redirected the focus of this research toward the conformational dynamics and intrinsic properties of PrPC itself, especially its role as an active participant in its own conversion.