Structural evidence for the critical role of the prion protein hydrophobic region in forming an infectious prion

Autoři: Romany Abskharon aff001;  Fei Wang aff003;  Alexandre Wohlkonig aff001;  Juxin Ruan aff003;  Sameh Soror aff001;  Gabriele Giachin aff006;  Els Pardon aff001;  Wenquan Zou aff007;  Giuseppe Legname aff008;  Jiyan Ma aff003;  Jan Steyaert aff001
Působiště autorů: Structural Biology Brussels, Vrije Universiteit Brussel (VUB), Brussels, Belgium aff001;  VIB-VUB Center for Structural Biology, Vlaams Instituut Biotechnologie (VIB), Brussels, Belgium aff002;  Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, Michigan, United States of America aff003;  National Institute of Oceanography and Fisheries (NIOF), Cairo, Egypt aff004;  Center of Excellence, Helwan Structural Biology Research, Faculty of Pharmacy, Helwan University, Cairo, Egypt aff005;  Structural Biology Group, European Synchrotron Radiation Facility, Grenoble, France aff006;  Departments of Pathology and Neurology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America aff007;  Laboratory of Prion Biology, Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), Trieste, Italy aff008
Vyšlo v časopise: Structural evidence for the critical role of the prion protein hydrophobic region in forming an infectious prion. PLoS Pathog 15(12): e32767. doi:10.1371/journal.ppat.1008139
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008139


Prion or PrPSc is the proteinaceous infectious agent causing prion diseases in various mammalian species. Despite decades of research, the structural basis for PrPSc formation and prion infectivity remains elusive. To understand the role of the hydrophobic region in forming infectious prion at the molecular level, we report X-ray crystal structures of mouse (Mo) prion protein (PrP) (residues 89–230) in complex with a nanobody (Nb484). Using the recombinant prion propagation system, we show that the binding of Nb484 to the hydrophobic region of MoPrP efficiently inhibits the propagation of proteinase K resistant PrPSc and prion infectivity. In addition, when added to cultured mouse brain slices in high concentrations, Nb484 exhibits no neurotoxicity, which is drastically different from other neurotoxic anti-PrP antibodies, suggesting that the Nb484 can be a potential therapeutic agent against prion disease. In summary, our data provides the first structure-function evidence supporting a crucial role of the hydrophobic region of PrP in forming an infectious prion.

Klíčová slova:

Animal prion diseases – Antibodies – Cell binding assay – Crystal structure – Crystallization – Enzyme-linked immunoassays – Lipids – Prion diseases


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