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

English version

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: https://doi.org/10.1371/journal.ppat.1008139

Souhrn

Prion or PrP^Sc is the proteinaceous infectious agent causing prion diseases in various mammalian species. Despite decades of research, the structural basis for PrP^Sc 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 PrP^Sc 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

Zdroje

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