A conformational switch controlling the toxicity of the prion protein

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

doi:10.1038/s41594-022-00814-7

Molecular BiologyNature Structural & Molecular BiologyAug 1, 2022

Peer-reviewed journal article

A conformational switch controlling the toxicity of the prion protein

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

Abstract

Prion infections cause conformational changes of PrPC 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 2-3 and {beta}2-2 loops of PrPC. Expression of a PrP2Cys mutant mimicking the H-latch was constitutively toxic, whereas a PrPR207A 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 PrPC, but not PrP2Cys. 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.

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