A conformational switch controlling the toxicity of the prion protein.
Creators: name: Frontzek, Karl
name: Bardelli, Marco
name: Senatore, Assunta
name: Henzi, Anna
name: Reimann, Regina R
name: Bedir, Seden
name: Marino, Marika
name: Hussain, Rohanah
name: Jurt, Simon
name: Meisl, Georg
name: Pedotti, Mattia
name: Mazzola, Federica
name: Siligardi, Giuliano
name: Zerbe, Oliver
name: Losa, Marco
name: Knowles, Tuomas
name: Lakkaraju, Asvin
name: Zhu, Caihong
name: Schwarz, Petra
name: Hornemann, Simone
name: Holt, Matthew G
name: Simonelli, Luca
name: Varani, Luca
name: Aguzzi, Adriano
Publisher: name: Apollo - University of Cambridge Repository
Year: 2022
Subjects: Article
/631/535/1267
/631/45/460
/13/1
/13/51
/14
/14/19
/38
/82
/101
/101/6
/82/80
article

description: Funder: Ono PharmaceuticalsTheodo Ida Herzog-Egli Stiftung
description: Funder: Stavros Niarchos Foundation (SNF); doi: https://doi.org/10.13039/501100004343
description: Funder: RCUK | Biotechnology and Biological Sciences Research Council (BBSRC); doi: https://doi.org/10.13039/501100000268
description: Funder: EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council); doi: https://doi.org/10.13039/100010663
description: Funder: Frances and Augustus Newman Foundation; doi: https://doi.org/10.13039/100007898
description: Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: “Ideas” Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199; Grant(s): H2020-WIDESPREAD-2018-2020-6; NCBio; 951923
description: Funder: FWO (Grant 1513616N)
description: Funder: Lions Club Monteceneri
description: Funder: Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation); doi: https://doi.org/10.13039/501100001711
description: Funder: Gelu Foundation, Swiss Initiative in Systems Biology, SystemsX.ch (PrionX, SynucleiX)
description: 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.