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.

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; Holt, Matthew G; Simonelli, Luca; Varani, Luca; Aguzzi, Adriano. - In: NATURE STRUCTURAL & MOLECULAR BIOLOGY. - ISSN 1545-9985. - 29:8(2022), pp. 831-840. [Epub ahead of print] [10.1038/s41594-022-00814-7]

A conformational switch controlling the toxicity of the prion protein

Losa, Marco;
2022-01-01

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.
2022
Animals
Antibodies
Cerebellum
Ligands
Mice
Prion Proteins
PrPC Proteins
Prions
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11768/132897
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