Novel quaternary structures of the human prion protein globular domain

Oliveira Bortot, L.; Lopes Rangel, V.; A. Pavlovici, F.; El Omari, K.; Wagner, A.; Brandao-Neto, J.; Talon, R.; von Delft, F.; G Reidenbach, A.; M Vallabh, S.; Vallabh Minikel, E.; Schreiber, S.; Cristina Nonato, M.

doi:10.1101/2020.11.16.385856

bioRxiv · 10.1101/2020.11.16.385856

Novel quaternary structures of the human prion protein globular domain

Oliveira Bortot, L.·Lopes Rangel, V.·A. Pavlovici, F.·El Omari, K.·Wagner, A.·Brandao-Neto, J.·Talon, R.·von Delft, F.·G Reidenbach, A.·M Vallabh, S.·Vallabh Minikel, E.·Schreiber, S.·Cristina Nonato, M.

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Abstract

Prion disease is caused by the misfolding of the cellular prion protein, PrPC, into a self-templating conformer, PrPSc. Nuclear magnetic resonance (NMR) and X-ray crystallography revealed the 3D structure of the globular domain of PrPC 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, PrPSc is composed by a complex and heterogeneous ensemble of poorly defined conformations and quaternary arrangements that are related to different patterns of neurotoxicity. Targeting PrPC 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 PrPC. Thus, it is essential to expand our structural knowledge about PrPC as much as possible to aid such drug discovery efforts. In this work, we report a crystallographic structure of the globular domain of human PrPC 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.

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Oliveira Bortot, L., Lopes Rangel, V., A. Pavlovici, F., El Omari, K., Wagner, A., Brandao-Neto, J., Talon, R., von Delft, F., G Reidenbach, A., M Vallabh, S., Vallabh Minikel, E., Schreiber, S., Cristina Nonato, M.. 2020-11-17. Novel quaternary structures of the human prion protein globular domain. https://doi.org/10.1101/2020.11.16.385856

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