A conformational switch controlling the toxicity of the prion protein

Frontzek, Karl; Bardelli, Marco; Senatore, Assunta; Henzi, Anna; Reimann, Regina R; 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

doi:10.1038/s41594-022-00814-7

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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., Losa, M., Knowles, T., Lakkaraju, A., Zhu, C., Schwarz, P., … Aguzzi, A. (2022). A conformational switch controlling the toxicity of the prion protein. Nature Structural & Molecular Biology, 29(8), 831–840. https://doi.org/10.1038/s41594-022-00814-7

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 represse