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

Angélique Igel-Egalon (1, 2) , Mohammed Moudjou (1, 2) , Davy Martin (1, 2) , Alexandra Busley (3, 2) , Tina Knäpple (3, 2) , Laetitia Herzog (1, 2) , Fabienne Reine (1, 2) , Nad'A Lepejová (3, 2) , Charles-Adrien Richard (1, 2) , Vincent Béringue (1, 2) , Human Rezaei (1, 2)

1 VIM (UR 0892) - Unité de recherche Virologie et Immunologie Moléculaires
2 Université Paris Saclay (COmUE)
3 VIRO - Virologie UMR1161

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 (Pr-PC). 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.

Domaines: Sciences du Vivant [q-bio]

Angélique Igel-Egalon, Mohammed Moudjou, Davy Martin, Alexandra Busley, Tina Knäpple, et al.. Reversible unfolding of infectious prion assemblies reveals the existence of an oligomeric elementary brick. PLoS Pathogens, 2017, 13 (9), ⟨10.1371/journal.ppat.1006557⟩. ⟨hal-02619876⟩