N-Glycosylation is a Potent Regulator of Prion Protein Neurotoxicity

Millhauser, G. L.

doi:10.1101/2023.02.25.530047

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bioRxiv · 10.1101/2023.02.25.530047

N-Glycosylation is a Potent Regulator of Prion Protein Neurotoxicity

Millhauser, G. L.

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Abstract

The C-terminal domain of cellular prion protein (PrPC) contains two N-linked glycosylation sites, the occupancy of which impacts disease pathology. In this study, we demonstrate that glycans at these sites are required to maintain an intramolecular interaction with the N-terminal domain, mediated through a previously identified copper-histidine tether, which suppresses the neurotoxic activity of PrPC. NMR and EPR spectroscopy demonstrate that the glycans refine the structure of the proteins interdomain interaction. Using whole-cell patch-clamp electrophysiology, we further show that cultured cells expressing PrP molecules with mutated glycosylation sites display large, spontaneous inward currents, a correlate of PrP-induced neurotoxicity. Our findings establish a structural basis for the role of N-linked glycans in maintaining a non-toxic, physiological fold of PrPC.

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Millhauser, G. L.. 2023-02-26. N-Glycosylation is a Potent Regulator of Prion Protein Neurotoxicity. https://doi.org/10.1101/2023.02.25.530047

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