A conformational switch controlling the toxicity of the prion protein

Frontzek, Karl; Bardelli, Marco; Senatore, Assunta; Henzi, Anna; Reimann, Regina; Bedir, Seden; Marino, Marika; Hussain, Rohanah; Jurt, Simon; Meisl, Georg; Pedotti, Mattia; Mazzola, Federica; Siligardi, Giuliano; Zerbe, Oliver; Losa, Marco; Knowles, Tuomas; Lakkaraju, Asvin; Zhu, Caihong; Schwarz, Petra; Hornemann, Simone; Holt, Matthew; Simonelli, Luca; Varani, Luca; Aguzzi, Adriano

doi:10.1101/2021.09.20.460912

Author:

Frontzek, Karl

Bardelli, Marco ; Senatore, Assunta ; Henzi, Anna ; Reimann, Regina ; Bedir, Seden ; Marino, Marika ; Hussain, Rohanah ; Jurt, Simon ; Meisl, Georg ; Pedotti, Mattia ; Mazzola, Federica ; Siligardi, Giuliano ; Zerbe, Oliver ; Losa, Marco ; Knowles, Tuomas ; Lakkaraju, Asvin ; Zhu, Caihong ; Schwarz, Petra ; Hornemann, Simone ; Holt, Matthew ; Simonelli, Luca ; Varani, Luca ; Aguzzi, Adriano

Abstract:

Summary

Prion infections cause conformational changes of PrP C and lead to progressive neurological impairment. Here we show that toxic, prion-mimetic ligands induce an intramolecular R208-H140 hydrogen bond (“H-latch”) altering the flexibility of the α2-α3 and β2-α2 loops of PrP C . Expression of a PrP 2Cys mutant mimicking the H-latch was constitutively toxic, whereas a PrP R207A mutant unable to form the H-latch conferred resistance to prion infection. High-affinity ligands that prevented H-latch induction repressed prion-related neurodegeneration in organotypic cerebellar cultures. We then selected phage-displayed ligands binding wild-type PrP C , but not PrP 2Cys . These binders depopulated H-latched conformers and conferred protection against prion toxicity. Finally, brain-specific expression of an antibody rationally designed to prevent H-latch formation, prolonged the life of prion-infected mice despite unhampered prion propagation, confirming that the H-latch is causally linked to prion neurotoxicity.