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A conformational switch controlling the toxicity of the prion protein.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Bardelli, Marco 
Senatore, Assunta 
Henzi, Anna 
Reimann, Regina R 

Abstract

Prion infections cause conformational changes of the cellular prion protein (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 α2-α3 and β2-α2 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 an important reporter of prion neurotoxicity.

Description

Keywords

Animals, Antibodies, Cerebellum, Ligands, Mice, PrPC Proteins, Prion Proteins, Prions

Journal Title

Nat Struct Mol Biol

Conference Name

Journal ISSN

1545-9993
1545-9985

Volume Title

29

Publisher

Springer Science and Business Media LLC
Sponsorship
Swiss National Science Foundation (157699, 179040, 310030, 166445)
Fondation Thierry Latran (Thierry Latran Foundation) (SOD-VIP)
European Research Council (250356, 713755, H2020-WIDESPREAD-2018-2020-6)