Novel quaternary structures of the human prion protein globular domain.

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.
Competing Interests: Declaration of competing interest X All authors have participated in (a) conception and design, or analysis and interpretation of the data; (b) drafting the article or revising it critically for important intellectual content; and (c) approval of the final version. X This manuscript has not been submitted to, nor is under review at, another journal or other publishing venue. X The authors have no affiliation with any organization with a direct or indirect financial interest in the subject matter discussed in the manuscript
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