Novel quaternary structures of the human prion protein globular domain

Abstract

Prion disease is caused by the misfolding of the cellular prion protein, PrP^C, into a self-templating conformer, PrP^Sc. Nuclear magnetic resonance (NMR) and X-ray crystallography revealed the 3D structure of the globular domain of PrP^C and the possibility of its dimerization via an interchain disulfide bridge that forms due to domain swap or by non-covalent association of two monomers. On the contrary, PrP^Sc is composed by a complex and heterogeneous ensemble of poorly defined conformations and quaternary arrangements that are related to different patterns of neurotoxicity. Targeting PrP^C with molecules that stabilize the native conformation of its globular domain emerged as a promising approach to develop anti-prion therapies. One of the advantages of this approach is employing structure-based drug discovery methods to PrP^C. Thus, it is essential to expand our structural knowledge about PrP^C as much as possible to aid such drug discovery efforts. In this work, we report a crystallographic structure of the globular domain of human PrP^C that shows a novel dimeric form and a novel oligomeric arrangement. We use molecular dynamics simulations to explore its structural dynamics and stability and discuss potential implications of these new quaternary structures to the conversion process.

Keywords: Amyloid; Anomalous scattering; Prion; X-ray crystallography.