Reversible unfolding of infectious prion assemblies reveals the existence of an oligomeric elementary brick

Mammalian prions, the pathogens that cause transmissible spongiform encephalopathies, propagate by self-perpetuating the structural information stored in the abnormally folded, aggregated conformer (PrPSc) of the host-encoded prion protein (PrPC). To date, no structural model related to prion assembly organization satisfactorily describes how strain-specified structural information is encoded and by which mechanism this information is transferred to PrPC. To achieve progress on this issue, we correlated the PrPSc quaternary structural transition from three distinct prion strains during unfolding and refolding with their templating activity. We reveal the existence of a mesoscopic organization in PrPSc through the packing of a highly stable oligomeric elementary subunit (suPrP), in which the strain structural determinant (SSD) is encoded. Once kinetically trapped, this elementary subunit reversibly loses all replicative information. We demonstrate that acquisition of the templating interface and infectivity requires structural rearrangement of suPrP, in concert with its condensation. The existence of such an elementary brick scales down the SSD support to a small oligomer and provide a basis of reflexion for prion templating process and propagation.
Author summary Prions are self-propagating assemblies with all necessary and sufficient replicative information stored in the 3D structure of the misfolded form of PrP called PrPSc. Since the emergence of the prion theory in the 80s, many attempts have been done to identify prion replicative information at molecular scale. Different models have been constructed based on a broad panel of experimental observations and some of them predict the existence of periodic elements constituting prion assemblies. Here, by using partial unfolding approaches, we trapped an oligomeric conformer that we called suPrP, which could constitute the elementary brick of prion assemblies. Once isolated, this elementary brick is devoid of infectivity. However, it becomes infectious once condensated into larger assemblies. The identification of the elementary PrP building block provides a new structural basis for understanding prion replicative information storage and spreading.