Abstract
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.
Highlights
Prion diseases, known as transmissible spongiform encephalopathies (TSEs), are a group of fatal neurodegenerative diseases affecting both humans and animals[1]
Prion disease is caused by the misfolding of normal prion protein (PrPC) to its pathogenic isoform, termed PrPSc
The first high-resolution MoPrP(89–230)Nb484 crystal was obtained at pH 6.0, and the structure was refined to 2.1 Å resolution
Summary
Known as transmissible spongiform encephalopathies (TSEs), are a group of fatal neurodegenerative diseases affecting both humans and animals[1]. The prion protein (PrP) exists in two forms: the physiological cellular isoform, PrPC, and the disease-associated infectious isoform, denoted as prion or PrPSc[2]. The conversion from normal PrPC to prion is the underlying pathogenic event of prion diseases[4]. Detailed three-dimensional (3D) structures of different mammalian PrPC have been solved[5,6,7], but little atomic-level information is available on the PrPSc structure except for a recent study that proposes the 4-rung β-solenoid architecture of PrPSc[8]. The molecular mechanisms of the conformational conversion of PrPC into infectious prions and other key neurodegenerative processes in prion diseases remain unclear, which is a road block for developing effective therapeutic strategies against these devastating neurodegenerative disorders[8]
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