Our lab uses advanced magnetic resonance, both NMR and pulsed EPR, to study how the cellular prion protein, PrPC, takes up the micronutrient copper, in turn stabilizing its domain structure and facilitating interaction with other neurodegenerative proteins.
Copper inhibition of PrP neurotoxicity
Copper coordinates to three His residues in the N-terminal toxic effector domain and one His in the regulatory domain. Segmental isotope labeling identified C-terminal His176 as essential for this interaction. https://www.biorxiv.org/content/10.1101/2025.05.01.651769v1
How PrPC interacts with Aβ
The cellular prion protein, PrPC, transports the Alzheimer’s Aβ peptide across the plasma membrane. Mixed isotope, pulsed EPR applied to the complex shows that Cu2+ is a necessary cofactor. https://doi.org/10.1016/j.jbc.2025.108311
Glycosylation of PrPC is neuroprotective
PrPC is N-glycosylated at Asn residues 180 and 196. These glycans stabilize the protein structure and inhibit the N-terminal toxic effector domain. https://doi.org/10.1016/j.jbc.2023.105101
Double Electron-Electron Resonance EPR for determining protein conformations
DEER EPR reveals distance-dependent couplings between engineered nitroxide spin labels. In this study, we applied DEER to directly measure conformational changes in the lysosomal cystine transporter, cystinosin. https://doi.org/10.1016/j.cell.2022.08.020
Demonstration of PrPC as an Aβ transporter
The Aβ peptide accumulates in Alzheimer’s disease. This work showed that monomeric Aβ binds to PrPC, resulting in its translocation across the plasma membrane. https://doi.org/10.1073/pnas.2009238117