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
Abstract
Abstract Prion infections cause conformational changes of the cellular prion protein (PrP C ) 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 PrP C . Expression of a PrP 2Cys mutant mimicking the H-latch was constitutively toxic, whereas a PrP R207A 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 PrP C , but not PrP 2Cys . 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.