A conformational switch controlling the toxicity of the prion protein

Frontzek, K.; Bardelli, M.; Senatore, A.; Henzi, A.; Reimann, R. R.; Bedir, S.; Marino, M.; Hussain, R.; Jurt, S.; Meisl, G.; Pedotti, M.; Mazzola, F.; Siligardi, G.; Zerbe, O.; Knowles, T. P. J.; Lakkaraju, A.; Zhu, C.; Schwarz, P.; Hornemann, S.; Holt, M. G.; Simonelli, L.; Varani, L.; Aguzzi, A.

doi:10.1101/2021.09.20.460912

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bioRxiv · 10.1101/2021.09.20.460912

A conformational switch controlling the toxicity of the prion protein

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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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Frontzek, K., Bardelli, M., Senatore, A., Henzi, A., Reimann, R. R., Bedir, S., Marino, M., Hussain, R., Jurt, S., Meisl, G., Pedotti, M., Mazzola, F., Siligardi, G., Zerbe, O., Knowles, T. P. J., Lakkaraju, A., Zhu, C., Schwarz, P., Hornemann, S., Holt, M. G., Simonelli, L., Varani, L., Aguzzi, A.. 2021-09-20. A conformational switch controlling the toxicity of the prion protein. https://doi.org/10.1101/2021.09.20.460912

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