Transient multimers modulate conformer abundances of prion protein monomer through conformational selection

Prions are known to be involved in neurodegenerative pathologies such as Creutzfeld-Jakob disease. Current models point to a molecular event which rely on a transmissible structural change that leads to the production of β-sheet-rich prion conformer (PrP^Sc). PrP^Sc itself has the capability to trigger the structural rearrangement of the ubiquitously present prion (PrP^c) substrate in a self-perpetuating cascade. In this article, we demonstrate that recombinant PrP^c exists in a conformational equilibrium. The conformers' abundances were shown to be dependent on PrP^c concentration through the formation of transient multimers leading to conformational selection. The study of PrP^c mutants that follow dedicated oligomerization pathways demonstrated that the conformers' relative abundances are modified, thus reinforcing the assertion that the nature of conformers' interactions orient the oligomerization pathways. Further this result can be viewed as the "signature" of an aborted oligomerization process. This discovery sheds a new light on the possible origin of prion protein diseases, namely that a change in prion protein structure could be transmitted through the formation of transient multimers having different conformer compositions. This could explain the selection of a transient multimeric type that could be viewed as the precursor of PrP^Sc responsible for structural information transmission, and strain apparition.