Open AccessStructural evidence for the critical role of the prion protein hydrophobic region in forming an infectious prion
Author(s) -
Romany Abskharon,
Fei Wang,
A. Wohlkonig,
Ju-Xin Ruan,
Sameh H. Soror,
Gabriele Giachin,
Els Pardon,
Wen-Quan Zou,
Giuseppe Legname,
Jiyan Ma,
Jan Steyaert
Publication year - 2019
Publication title -
plos pathogens
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.719
H-Index - 206
eISSN - 1553-7374
pISSN - 1553-7366
DOI - 10.1371/journal.ppat.1008139
Subject(s) - infectivity , prion protein , recombinant dna , infectious agent , neurotoxicity , scrapie , proteinase k , virology , chemistry , fungal prion , antibody , biology , microbiology and biotechnology , biophysics , biochemistry , virus , enzyme , genetics , disease , toxicity , phenotype , medicine , pathology , organic chemistry , gene
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.